Apoptosis and cell death; Bioinformatics; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Regulation of metabolism
My laboratory studies the cell-autonomous and non-cell-autonomous mechanisms of axon degeneration, a process akin to programmed cell death. In other words, we are attempting to elucidate what causes axon breakdown from within neurons and which external (glial) events trigger axon loss. Degeneration of axons is a hallmark in many neurodegenerative conditions, including those associated with abnormal glia. We have great hope that understanding why and how axons degenerate may lead to more efficient neuroprotective therapies tailored specifically to support axons and their surrounding glia. Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system. As such, they are critical for neuronal wiring and transport of neuronal maintenance signals. Because of their incredible length and energetic demand (human motor neurons can be one meter long), however, axons are very vulnerable and at continuous risk of damage. Axons do not exist in isolation but are inextricably and intimately associated with their enwrapping glia (Schwann cells and oligodendrocytes) to form a unique axon-glia unit. The most relevant neurological symptoms in a number of debilitating neurodegenerative conditions are due to compromised axon integrity. Thus, neuroprotective therapies promoting axon stability have great potential for more effective treatment. Recent studies indicate that axonal degeneration, at least in experimental settings, is an active and highly regulated process akin to programmed cell death (‘axonal auto-destruction’). Moreover, it is increasingly realized that axonal maintenance relies not only on neuron-derived provisions but also on trophic support from their enwrapping glia. The mechanism for this non-cell-autonomous support function remains unknown, but emerging evidence indicates that it is distinct from the glial role in insulating axons with myelin. We are pursuing the intriguing question of whether abolished support by aberrant delivery of metabolites and other trophic factors from glia into axons is mechanistically linked to the induction of axonal auto-destruction. This concept is supported by our recent finding that metabolic dysregulation exclusively in Schwann cells is sufficient to trigger axon breakdown.
Bioinformatics; Ion channel kinetics and structure; Molecular and Cellular Biology
Research in my lab focuses on ion channels. I am interested in how interventions such as ancillary subunits, mutations, drugs, and environmental changes affect the structure-function relationship, and ultimately how this affects cellular electrical activity. We do this using a combination of techniques and approaches including 2 electrode clamp to study heterologously expressed channels, whole cell clamp to record currents in the native cell, and mathematical modelling to understand and interpret results.
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Our research group is interested in how regulatory proteins are targeted to the correct DNA binding sites at the correct time. Transcription factors are directed to their genomic targets by DNA sequence, local chromatin structure, and protein-protein interactions. These modulators of transcription factor binding are not independent but function both cooperatively and competitively to regulate where transcription factors bind. Understanding how these modulators affect transcription factor binding in vivo remains a major unsolved biological problem. We use the model organism Saccharomyces cerevisiae to address the disconnect between the presence of the correct DNA binding sequence and true regulatory protein binding, integrating both experimental and computational approaches to: i) investigate transcription factor binding in response to environmental stress, ii) identify and characterize the mechanisms directing transcription factor target selection, and iii) and develop bioinformatics tools to analyze and interpret ChIP-seq experiments and chromatin structural patterns.
Computational Chemistry; Drug Design; Structural Biology; X-ray Crystallography; Bioinformatics; Protein Folding
The long-term goal of my research has been to understand the role of key active site residues in the mechanism of molecular recognition among various classes of proteins. The primary focus has been study of folate-dependent enzyme pathways, in particular dihydrofolate reductase (DHFR). These enzymes from pathogenic Pneumocystis species are of interest for the design of selective inhibitors for the treatment of AIDS-related pneumonia. Analysis of the structural data from several classes of protein has revealed a great degree of conformational flexibility for ligand binding that result in novel modes of binding to the same active site. Understanding the role of such flexibility has aided in the design of new scaffolds for inhibitor design. Additionally, my lab has the expertise to carry out the necessary molecular biology experiments to clone, express and purify proteins for crystallographic study using both bacterial and insect cell host systems. We have a long-standing, successful collaboration with the Queener lab to study DHFR, particularly from the opportunistic pathogens Pneumocystis jirovecii (pj) and Pneumocystis carinii (pc), found in man and rats, respectively. Our lab is also studying transthyretin (TTR), the thyroid hormone transport protein, characterizing the human protein bound to inhibitors with potential to stabilize the tetrameric structure and ameliorate the effects of filbril formation. Transthyrtetin from lamprey is of interest as it is thought to be the cross-over species in the change of function from a hydrolase to hormone transport function.
Autoimmunity; Bioinformatics; Genomics and proteomics; Immunology; Infectious Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology
My primary research is in the field of biomedical ontology development. An ontology is a controlled, structured vocabulary intended to represent knowledge within a particular domain. Terms in an ontology have logical relationships to each other and to terms in other ontologies, to allow for reasoning and inference across the ontology. Biomedical ontologies allow annotation and integration of scientific data within particular fields of science and medicine, and their careful curation and logical structure facilitate data analysis. My work in biomedical ontology is strongly informed by my earlier experience in laboratory research in immunology, genetics, molecular biology and virology. My research group works on ontologies for both basic and clinical applications, in collaboration with researchers both at UB and other institutions. I led efforts to revise and extend the Cell Ontology, which is intended to represent in vivo cell types from across biology. We worked extensively to bring it up to community-accepted standards in ontology development, placing particular emphasis on improving the representation of hematopoietic cells and neurons. We are developing the Cell Ontology as a metadata standard for annotation and analysis of experimental data in immunology in support of the National Institute of Allergy and Infectious Diseases (NIAID) ImmPort Immunology Database and Analysis Portal and Human Immunology Project Consortium. We have also developed ways to use the Cell Ontology in support of the analysis of gene expression data linked to cell types and have contributed to the Functional Annotation of the Mammalian Genome (FANTOM) 5 Consortium‘s work on identifying gene transcription start sites across multiple cell types and tissues. My research team is also developing the Neurological Disease Ontology to represent clinical and basic aspects of neurological diseases in order to support translational research in this area. In collaboration with clinical colleagues at UB, we are initially focusing on Alzheimer’s disease and dementia, multiple sclerosis and stroke. We have as well developed a companion ontology, the Neuropsychological Testing Ontology, to aid in the annotation and analysis of neuropsychological testing results used as part of the diagnosis of Alzheimer‘s disease and other neurological diseases. I am a long-term member of the Gene Ontology (GO) Consortium and have a particular interest in the representation of immunology and neuroscience in the GO. I am also involved in UB’s contribution to the Protein Ontology and contribute as well to the work of the Infectious Disease Ontology Consortium, Immunology Ontology Consortium and Vaccine Ontology Consortium. I teach and mentor students at the master’s and doctoral levels, and advise undergraduate, graduate, and medical students in summer research projects as well.
Bioinformatics; Genomics and proteomics; Immunology; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression
The current focus of my lab is on iron metabolism in animals and humans. From the practical viewpoint, iron is an important nutrient, but its ability to act in the ferrous and ferric state also makes it toxic. Thus, iron deficiency is the most frequent disorder in the world and hereditary hemochromatosis (HH) is the most common Mendelian disorder in the United States. Our research is related to erythroid differentiation on the fundamental level and to genetic and acquired diseases on the applied level, with four long-term themes: 1.) analysis of the molecular basis of differential gene expression among tissues and during development, with hemoglobin synthesis and red blood cell (RBC) development as models; 2.) application of molecular and genetic advances to inherited diseases; 3.) iron metabolism; 4.) study of gene variation in populations and divergence of gene loci during evolution. New vistas have opened recently for the anemia of chronic diseases, leading us to re-exam how microbes and their human hosts fight for iron. We approach these issues by working on rodent models like the Belgrade rat, plus a series of genetically engineered mice. The rat has a hypochromic, microcytic anemia inherited as an autosomal recessive. The defect is in an iron transporter called DMT1 (or slc11a2, previously called Nramp2 or DCT1) that is responsible for iron uptake by enterocytes and is also responsible for iron exiting endosomes in the transferrin cycle. The rats appear to have a severe iron deficiency, and although dietary iron and iron injection increase the number of RBCs, they do not restore the RBCs nor the rat itself to a normal phenotype. Recent discoveries show that DMT1 is ubiquitous and responsible for transport of other metals such as Mn and Ni. It occurs in the kidney, brain and lung at even higher levels than in the GI tract or in erythroid cells. It also has multiple isoforms, and we have cloned them and developed cell lines that express high levels of particular isoforms. We have specific antibodies to the isoforms and assays for each of the mRNAs too. Future projects in my lab will continue to address whether DMT1 is dysregulated in HH. We will also tackle how DMT1 functions in neurons, pneumocytes and other tissues, look at isoforms of DMT1 under circumstances where we suspect that they must have different functions from one another, and examine DMT1’s relevance to iron metabolism and human disease. Because we cloned the gene and identified the mutation, a number of molecular and cellular approaches can now be used. As evidence indicates that metal ion homeostasis fails in Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, research on DMT1 has opened new vistas for these disorders.
Bioinformatics; Cell growth, differentiation and development; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression; Stem Cells; Transgenic organisms
My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans. We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication? These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development. When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants. In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Signal Transduction
Research in my laboratory investigates the genetic regulatory circuitry that controls how cell fates are determined during development. We focus on two key aspects, intercellular signaling and transcriptional regulation, using primarily the fruit fly Drosophila melanogaster due to its extremely well-annotated genome and amenability to experimental manipulation. All conclusions, however, are expected to relate directly to mammalian (including human) gene regulation. Recently, we have also started investigating the regulatory genomics of other insect species of both medical and agricultural importance, beginning with the development of methods for regulatory element discovery in species with fully sequenced genomes but little functional, experimental data. A defining feature of my laboratory is that it takes both wet-lab and computational/bioinformatics approaches to studying the same set of problems about development and transcriptional regulation; hypotheses and ideas generated using one set of methods are tested and explored using the other. Current research in the laboratory falls into two main areas: 1) discovery and characterization of transcriptional cis-regulatory modules (CRMs), and 2) mechanisms of specificity for receptor tyrosine kinase (RTK) signaling. The combined results of these studies will provide insight into gene regulation, genome structure, intercellular signaling, and the regulatory networks that govern embryonic development. My group is also heavily involved in biocuration through our development and maintenance of REDfly, an internationally-recognized curated database of known Drosophila transcriptional cis-regulatory modules (CRMs) and transcription factor binding sites (TFBSs). Despite more than 25 years of experimental determination of these elements, the data have never been collected into a single searchable database. REDfly seeks to include all experimentally verified fly regulatory elements along with their DNA sequence, their associated genes, and the expression patterns they direct. REDfly is by far the most comprehensive database of regulatory elements for the higher eukaryotes and serves as an important resource for the fly and bioinformatics communities.
Anatomic Pathology; Blood Banking/Transfusion Medicine; Clinical Pathology; Cytopathology; Hematology - Clinical Pathology; Immunopathology; Surgical Pathology; Toxicology; Transfusion Medicine; Bioinformatics; Microbiology; Virology
I serve the Department of Pathology and Anatomic Sciences as a general pathologist in anatomic and clinical pathology. My primary areas for service work include surgical pathology and cytopathology as an attending pathologist rotating among the Kaleida hospital sites and clinical pathology activities in clinical chemistry, transfusion medicine, microbiology and hematology. I serve as the laboratory medical director for the clinical laboratories at the Women and Children‘s Hospital of Buffalo and the Center for Laboratory Medicine, Williamsville (Flint). I also provide more specialized medical support for the forensic toxicology laboratory at the Women and Children‘s Hospital, the fetal defect screening program at the Center for Laboratory Medicine in Williamsville, the Virology laboratory at Women and Children‘s Hospital and the Therapeutic Plasmapheresis program at the Buffalo General Medical Center. I have developed an interest in Clinical Informatics and regularly employ those skills to retrieve and analyze data from Kaleida and elsewhere to support clinical decision making, research activities, EHR development and business development. Within the department, I am the pathologist overseeing the Transfusion Service across Kaleida and also provide pathology direction to the Kaleida Clinical Chemistry and Microbiology programs. In addition, I support the leadership of Kaleida in their Utilization Program, the Gainsharing Program, Peer Review and as Chair of the Site specific Transfusion Committees. Since January 2013 I have also served as the laboratory director of the Erie County Public Health Laboratory. Previously I have served as the laboratory director at the Center for Laboratory Medicine, Amherst (Suburban), Buffalo General Hospital and as an assistant laboratory director at Gates Circle. Each of these positions has been valuable to me in learning how different groups work together and how different groups of clinicians see and set expectations for a pathology department. Outside of Kaleida, I serve the region as representative to the Erie County Medical Society Legislative Committee and the Economic Affairs Committee. I have also served as president of the Western New York Society of Pathologists (1999-2000) and as Delegate to the College of American Pathologists House of Delegates (2005 - present). The overall theme of these activities is to leverage the skills cultivated by any practicing pathologist to recognize patterns. Those patterns recognized are then directed to purposes that can be quite diverse, ranging from diagnosis to data integrity. Data retrieved from multiple sources are used to provide an unbiased review for departmental and hospital leaders to troubleshoot, drive test menus or to review patterns of practice. Good data can drive good decisions, but only to the degree that the data can be recognized and understood. My professional time is divided in four parts, with anatomic pathology service work comprising about one quarter of my time, clinical pathology service work a second quarter, administrative activities a third quarter and clinical informatics the last quarter (plus or minus 5%), but with the added bonus that on any one day, these duties can shift dramatically to address the needs of the department and hospital. One of the most rewarding parts of my career has been the opportunity do all of these to the best of my ability and to support the efforts of the excellent professionals around me. The variety of responsibilities I have translate into a job that is never dull. I have used my own situation as a model for the pathology residents I train to provide a live demonstration that the field of Pathology is big enough to have something of interest for any interested person.
Infectious Disease; Bioinformatics; Microbial Pathogenesis
My clinical interest work focuses on infectious diseases, particularly those caused by Staphylococcus aureus. I practice medicine at the VA Western New York Healthcare System, where I am Chief of the Infectious Disease Section. The service here treats veterans with a wide variety of infectious diseases, including HIV and hepatitis C. I follow both inpatients and outpatients on this clinical service. Medical students, residents, and fellows evaluate and follow infectious disease consultations with me on the inpatient service. I teach extensively in the Medical School, and serve as Vice Chair for Education in the Department of Medicine. I enjoy working with students throughout the full spectrum of medical education, from first-year medical students to senior fellows in Infectious Disease. My research interests dovetail with my clinical work. I study Staphylococcal infections, particularly complications related to S. aureus bloodstream infections. My laboratory uses advanced molecular biology techniques to identify bacterial virulence factors. In collaboration with Steve Gill at the University of Rochester, we are analyzing three years of clinical data on S. aureus bacteremia in the Buffalo area and sequencing hundreds of bacteremia isolates of S. aureus to identify the genomic architectures associated with more severe complications and those associated with poor clinical outcomes. This work makes use of bioinformatics and database design, techniques that support my ongoing collaborations with other investigators on bioinformatics problems, particularly with Moraxella catarrhalis and Haemophilus influenzae. Prior to my studies in S. aureus, I conducted research on a fascinating pathogen, H. influenzae bio group aegyptius and Brazilian Purpuric Fever. Over that 10-year period my laboratory identified a unique epitope on a surface proteins associated with the disease. We were able to create the only isogenic mutant so far described with this pathogen that is highly refractory to genetic manipulation.
Bioinformatics; Gene Expression; Genomics and proteomics
My research is focused on developing bioinformatics algorithms especially through sequencing analysis and data integration, to understand better transcriptional and epigenetic regulation. Transcription factor often binds to DNA and interferes with transcription machinery to enhance or repress gene expression. Epigenetic features such as histone modification, chromatin remodeling factor binding, DNA methylation, and chromatin 3D organization add yet another layer of information, making it more complex to understand the regulation dynamics within the nucleus. With advancing sequencing technology, however, such information now can be measured and quantified in genome scale, though the growing number of big genomic datasets creates challenges as well as opportunities for bioinformatics methodologies. The focus of our lab is to build algorithms, analysis platforms and databases to integrate big datasets from the public domain into various biological questions and disease models. The MACS (Genome Biology 2008) algorithm, on which I worked to develop, is one of the most widely-used algorithms for predicting cis-regulatory elements from Chromatin Immunoprecipitation with high-throughput sequencing (ChIP-seq). The algorithm has been evolving over years to accommodate various factor types from punctuate transcription factor binding to long-range histone modifications. It has been used to process hundreds of publicly-available datasets in the mod/ENCODE project, and it continues as a focus of my lab. I also worked to build an integrative platform for ChIP analysis based on Galaxy framework, named Cistrome (Genome Biology 2011). This platform provides both a user-friendly interface and rich functionality for biologists to manage and process their high-throughput genomic data and to publish the results conveniently over the Internet. The Cistrome platform will continue as a collaborative project between my UB lab and research partners at Harvard University. I have also been involved in many collaborative research projects, such as circadian binding of histone deacetylase and nuclear receptor Rev-Erba in mouse liver (Science 2011), and the modENCODE consortium project to elucidate chromatin factor functions of C. elegans (Genome Research 2011 and Science 2010).
Apoptosis and cell death; Bioinformatics; Endocrinology; Gene Expression; Gene therapy; Genomics and proteomics; Immunology; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; RNA; Viral Pathogenesis
Dr. Mahajan has established herself as an investigator in the area of neuropathogenesis of HIV-1 in the context of drug abuse. She has initiated several new projects that investigate the role of a unique key signaling molecule in the dopaminergic pathway that impacts drug addiction, depression and other neurological disorders. Her focus has always been on collaborative, interdisciplinary partnerships between various Departments within UB that include the Institute of Lasers, Photonics and Biophotonics, Research Institute of Addiction, Dept of Computer Science and Engineering, Dept of Pharmaceutical sciences and the Department of Bioengineering. This inclusive strategy has facilitated the emergence of a robust, innovative clinical translational research program for our Division that continues to grow steadily. Dr Mahajan has obtained independent research funding from NIDA, the pharmaceutical Pfizer, US- Fulbright and other Private Foundations such as Dr. Louis Skalrow Memorial trust to conduct some of these research projects. Dr. Mahajan is Director of Research of the Division of Allergy, Immunology & Rheumatology. She supervises the research training of the Allergy fellows,Medical residents, graduate and undergraduate students. Dr. Mahajan has presented her research work at National and International conferences and was an invited speaker at several seminars and colloquiums. She has authored over 95 publications in several top quality peer reviewed journals and has thus demonstrated a high level of scholarly productivity. She is a reviewer and an adhoc member of the editorial board of several journals in her field. The following is a brief synopsis of her research interests. HIV neuropathogenesis in the context of drug abuse: We proposed that Opiates act as co-factors in the pathogenesis of HIV-1 infections by directly suppressing immune functions of the host through interactions with mu-opioid receptors on lymphocytes. Exacerbation of HIV encephalopathy (HIVE) is observed with opiate abuse. The mechanisms underlying HIVE are currently undetermined however, they likely to include the generation of endogenous neurotoxins combined, perhaps synergistically, with bioreactive HIV-1 envelope proteins. We believe that these proposed mechanisms may work through a common signal transduction mechanism activating dopamine D1 receptors in the nucleus accumbens of the brain. Opiate abuse by HIV-1 infected subjects may exacerbate the progression of HIVE as a consequence of the combined effects of HIV-1 induced neurotoxins plus opiate induced increases in the D1 receptor activation. We hypothesize that the dopaminergic signaling pathway is the central molecular mechanism that integrates the neuropathogenic activities of both HIV-1 infections and the abuse of opiate drugs. In this context our investigation is focused on the DARPP-32 signalling pathway. Addictive drugs act on the dopaminergic system of the brain and perturb the function of the dopamine- and cyclic-AMP-regulated phosphoprotein of molecular weight 32 kD (DARPP-32). DARPP-32 is critical to the pathogenesis of drug addiction by modulating both transcriptional and post-translational events in different regions of the brain. DARPP-32 is localized within neurons containing dopamine receptors and is a potent inhibitor of another key molecule in the dopaminergic signaling pathway, protein phosphatase 1 (PP-1). We propose that the sustained silencing of DARPP-32 gene expression using specific siRNA delivered to the brain is an innovative approach for the treatment of drug addiction. The specific challenge of the proposed project is the non-invasive delivery of biologically stable, therapeutic siRNA molecules to target cells within the brain. We are developing biocompatible nanoparticles to both protect DARPP-32 specific siRNA against degradation and deliver it from the systemic circulation across the BBB to specific dopaminergic neurons in the brain of patients with opiate addictions. BBB Research: While examining neuropathogenesis of HIV, we became interested in the role of the blood-brain barrier (BBB) in HIV neuropathogenesis with the objective of developing therapeutic interventions to prevent and limit the progression of HIV associated neurological disease. The blood-brain barrier is an intricate cellular system composed of vascular endothelial cells and perivascular astrocytes that restrict the passage of molecules between the blood stream and the brain parenchyma. We evaluated and validated both the 2 and 3 dimensional human in-vitro BBB models in my laboratory, that allowed examining permeability of virus, effects of drugs of abuse on BBB permeability, mechanisms of BBB transport, and tight junction modulation. Our goal remains to determine the impact of current and potential CNS antiretrovirals, psychopharmacologic, and other medications on the integrity of the BBB in HIV associated neurological disorder and other neurodegenerative diseases. Additionally, We also investigate mechanisms that underlie drugs of abuse induced neuronal apoptosis. Systems biology approach: We expanded our investigation to include functional genomic/proteomic analyses that allowed characterization of gene/ protein modulation in response to a drug stimulus or under a specific disease condition. We developed an expertise in these large-scale genomic and proteomic studies and the genomic studies helped identify key genes that underlie molecular mechanisms in drug addiction, HIV diseases progression, and allowed examination of the interplay of genes and environmental factors. The proteomic studies confirmed the presence of specific proteins that regulate key biological processes in drug addiction and HIV diseases progression. Recently, We have expanded my research program to include microbiome analyses and incorporated the utility of the computational drug discovery platform (CANDO) model that allows studying interaction between protein structures from microbiome genomes and determine the interactions that occur between them and small molecules (drugs and human/bacterial metabolites that are already a part of or continue to be added to the CANDO library. Using the CANDO Platform we are able to do the hierarchical fragment-based docking with dynamics between those compounds/drugs and the microbiome proteins/proteomes to determine which ones of the drugs and metabolites will work most efficaciously in patients using specific drugs. NanoMedicine: Over the last couple of years, We have become increasingly interested in nanomedicine and have developed several interdisciplinary clinical translational research focused collaborations that include 1) Nanotechnology based delivery systems to examine antitretroviral transport across the BBB; 2) Nanotherapeutics using siRNA/Plasmid delivery to specific regions in the brain to target various genes of interest specifically those pertaining to the dopaminergic pathway that includes a phosphor protein called “DARPP-32”. Targeting various key genes in the dopaminergic pathway results in the modulation of behavioral response which we observed in animal models of addiction/depression, 3) Biodistribution studies of various nanotherapeutic formulations using PET small animal imaging. Additionally, We are also focused on exploring epigenetic mechanisms that under drug addiction and mechanisms that underlie oxidative stress in neurodegenerative diseases.
Critical Care Medicine; Pulmonary & Critical Care Medicine; Internal Medicine; Pulmonary Disease; Pulmonary; Bioinformatics
I am engaged in clinical, teaching and research responsibilities related to the evaluation and treatment of patients with pulmonary disease or patients who are critically ill. My inpatient practice is primarily located at the medical intensive care unit (MICU) at the Buffalo General Medical Center (BGMC). The MICU provides ongoing medical care to patients who are critically ill and require significant life support therapies to sustain life or vital bodily functioning. I am specifically interested in asthma, COPD and lung cancer, but deal with a variety of disease. I evaluate patients with pulmonary disorders including shortness of breath, lung masses, abnormal chest imaging, abnormal pulmonary function tests, chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease, pulmonary hypertension and lung cancer, at the lung and heart outpatient clinic located in BGMC. The pulmonary team to which I belong also provides inpatient pulmonary consultation at both BGMC and Roswell Park Cancer Institute. Currently I am pursuing additional training in the analysis of Big Data in medical/healthcare fields. I am particularly focused on the application of drug repurposing in translation and clinic research. I also am heavily focused on the specific analysis of large VA associated clinical and genomic data sets as a fellow in the VA and NCI sponsored Big-Data Scientist Enhancement Program. I am engaged in the study of the human airways microbiome and metagenome. The human microbiome is the the collection of all the microbial organisms in a human body, and the corresponding metagenome is the collection of the genes, and gene products of the microbes. Due the potential impact of the microbiome on human health and disease, I am interested in studying the putative effects the interaction with human hosts, specifically innate immunity interaction with the metagenome in lung disease. Additionally, I collaborate with the Division of Allergy and Immunology and the Institute of Laser, Photonics and Biophotonics to elucidate immune cell function in airway diseases such as asthma and COPD. Our research focuses on the development of therapeutics aimed at novel targets identified as important in the molecular basis of pulmonary disease; efficacious laboratory results will generate more effective treatment plans for patients. I am actively involved in teaching medical students, residents and fellows about the appropriate care of the critically ill patient, as these trainees rotate in the MICU.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
We are interested in the fundamental mechanisms underlying the shift of cellular states from progenitors to fully functional mature cell types along individual cell lineages during development. We address this issue by studying cell fate specification and differentiation in the developing neural retina. Our efforts are on identifying key regulators, uncovering their roles in individual lineages, and understanding how they carry out these roles. Current projects are emphasized on how transcription factors influence the epigenetic landscape along the retinal ganglion cell lineage. We conduct our research using a combined approach of genetics, molecular biology, genomics, single cell analysis and bioinformatics.
Anatomic Pathology; Autopsy; Clinical Pathology; Cytopathology; Dermatopathology - Anatomic Pathology; Immunopathology; Medical Microbiology; Surgical Pathology; Bioinformatics; Microbiology
I pursued undergraduate and graduate education in biomedical engineering because of my interest in the application of basic science to solve real world problems. My studies included biomaterials and medical imaging. An interest specifically in medical science led me to medical school and eventually into pathology. After close to four years practicing community pathology, a desire to reestablish connections with UB pathologists initiated during my Roswell Park fellowship brought me back to Buffalo as a UB pathologist. My clinical responsibilities include surgical pathology, cytopathology, autopsy pathology and clinical pathology. I routinely work with pathology residents during their surgical pathology, cytology and autopsy rotations. I have particular interest in dermatopathology and gastrointestinal pathology. Image processing and analysis and bioinformatics also intrigue me. I am currently searching for new opportunities to collaborate with faculty in the anatomical sciences half of our department.
Bioinformatics; Cell growth, differentiation and development; Neurobiology
My laboratory seeks to understand the transcriptional regulatory network governing the differentiation of oligodendrocytes and central nervous system (CNS) myelination, with the long-term goal of translating this knowledge into the treatment of demyelinating diseases. CNS myelination by oligodendrocytes is important not only for saltatory conduction of action potentials but also for trophic support of nerve axons. An improved understanding of how the differentiation of oligodendrocytes is regulated for CNS myelination should provide a firm basis on which to develop more effective therapeutics for demyelinating diseases. Toward this goal, we are currently pursuing two different research directions. The first is to elucidate the functional mechanism of Myrf, a key transcription factor for CNS myelination. Conditional knockout mice in which Myrf is knocked out in the oligodendrocyte lineage cells completely fail to develop CNS myelin and exhibit severe neurological symptoms, eventually prematurely dying. Recently, we and the Emery laboratory have independently made the surprising discovery that Myrf is generated as an integral membrane protein that is auto-cleaved by its ICA domain into two fragments. This discovery invokes a number of fundamental questions about how Myrf drives the differentiation of oligodendrocytes for CNS myelination. We employ both computational and experimental laboratory methodologies to elucidate the functional mechanism of Myrf. The second direction is to identify new transcription factors for CNS myelination. By taking advantage of our computational expertise, we have performed integrated computational analysis of functional genomics data that are publicly available to predict a number of new transcription factors for oligodendrocyte differentiation. We are currently characterizing them using primary oligodendrocyte cultures. Promising hits will be further analyzed by generating knockout mice to test for in vivo relevance.
Over the past 30 years, my outpatient focus has been the care and management of patients with complex glomerular and autoimmune diseases. I serve as attending physician on the renal consult services for UBMD Nephrology at Buffalo General Medical Center, Roswell Park Cancer Institute and Erie County Medical Center (ECMC). I am also an attending physician on the inpatient Medicine A (General Medicine) and D (Renal Medicine) services at ECMC. My research concentrates on understanding mechanisms that underlie kidney disease, including the role of the complement system, a major factor in the body‘s immune response. My lab has developed and studied animal models of systemic lupus erythematosus, diabetic nephropathy, glomerulonephritis, obstructive nephropathy and acute renal failure. In addition to modeling disease in animals, we also have performed clinical studies both for promising new therapies and for those that focus on examining gene profiles from diseased renal tissue. To answer questions that arise in the course of our research, our work spans a number of disciplines and utilizes state-of-the-art approaches such as mouse kidney transplantation, 15-color flow cytometry and magnetic resonance imaging. My original degree is in mathematics, which remains a passion of mine. I also am interested in computational biology and founded the Computation Biology Core Facility at the University of Chicago. The core strength and emphasis of UB in the area of clinical informatics was a key factor in my decision to accept a position here so that I can continue to contribute to projects related to this field. In collaboration with leadership from other disciplines at UB, I helped establish one of the first clinical informatics fellowship programs in the United States. As a result, we accepted in 2014 the first joint nephrology/clinical informatics trainee in the country. As an educator, I am committed to the career development of the students, trainees and faculty working with me in my lab, in clinical research areas, in clinical informatics and in the clinical arena. Over the course of my career, I have mentored many outstanding students, fellows and faculty. Under my leadership and guidance, a number have received nationally competitive awards, and many have gone on to become academic leaders--including one who became a medical school dean. I serve on the Kidney, Urologic and Hematologic Diseases Subcommittee of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which critically evaluates training in nephrology. Through this commitment, I help ensure continued quality improvement in nephrology training, both nationally and at UB.
Bioinformatics; Genomics and proteomics; Signal Transduction; Toxicology and Xenobiotics
Our laboratory seeks to understand hormone-triggered nuclear receptor signaling. Nuclear receptors are associated with various diseases including diabetes and cancer and the availability of several high resolution structures of their ligand binding domains make them attractive targets for drug discovery. Eight of the top 100 prescription drugs (accounting for about US $9 billion in sales) target a nuclear receptor. However, these drugs can cause a variety of side effects and some patients develop drug resistance. Tamoxifen, a drug designed to selectively target the nuclear estrogen receptor which is present in 70% of breast cancer patients, induces substantial regression of breast tumors and an increase in disease-free survival. Tamoxifen binds directly to the ligand binding domain of estrogen receptor and regulates estrogen-mediated growth of breast cancer cells. Tamoxifen mimics estrogen effects in other tissues thereby providing some beneficial effects including reduced risk of osteoporosis. However, breast cancers that initially respond well to tamoxifen tend to develop resistance and resume growth despite the continued presence of the antagonist. We specifically focus on protein interactions that regulate estrogen signaling by binding to estrogen receptors. Our objective is to identify the estrogen receptor conformation-sensing regions of the interacting proteins and to discover potential small molecule sensors using state-of-the art bioinformatics and structure-based discovery tools and use them to generate a new breed of small molecular therapeutics for breast cancer therapy.
My group performs research to understand, through multiscale modelling, how organismal metagenomes specify their behavior and characteristics in conjunction with their environments. We accomplish this by developing novel computational biology and bioinformatics algorithms for predicting protein and proteome structure, function, interaction, design and evolution. We apply these basic science techniques to important practical problems in medicine, genetic and genomic engineering and nanobiotechnology. I received the 2010 National Institutes of Health (NIH) Director‘s Pioneer Award to develop the Computational Analysis of Novel Drug Opportunities (CANDO) platform (http://protinfo.org/cando/) to repurpose drugs approved for other indications in a shotgun manner. Our integrated informatics platform determines interactions between and among all drugs and all protein structures to create compound-proteome interaction signatures. The compound-proteome interaction signatures are weighted using pharmacological, physiological and chemoinformatics data and compared and analyzed to predict the likelihood of the corresponding compounds being efficacious for all indications simultaneously, in effect inferring homology of drug behavior at a proteomic level. Using this approach, we have made predictions for all the indications that our library of drugs maps to, with benchmarking accuracies that are two orders of magnitude better than what is observed when using random controls. We have performed prospective in vitro validations of our predictions, demonstrating comparable or better inhibition than existing drugs approved for clinical use in indications such as dengue, dental caries, diabetes, hepatitis B, herpes, lupus, malaria and tuberculosis. Our approach may be generalized to compounds beyond those approved by the FDA, and it can as well consider mutations in protein structures to enable precision medicine. We have also applied our computational techniques to design peptides for vaccines, antibacterial activity and inorganic substrate adhesion and model the structures, functions and interactions of all tractable proteins encoded by several rice genomes. A consistent theme in our research is the combination of in virtuale simulation and homology inference, followed by in vitro and in vivo verification and application, directed toward holistic multiscale modelling of complex biological systems.
Biomedical Image Analysis; Biomedical Imaging; Bioinformatics
I have worked in three distinct research domains in my career: analytical statistical signal processing, experimental molecular imaging, and genomic data analysis. I collaborate with researchers from both academia and industry in multiple disciplines, including theoretical and applied physics, biochemistry, cell biology, molecular biology, and medicine. This multidisciplinary, cross-sector experience has given me unique skills and tools for successfully executing the goals of my laboratory. The major projects in my laboratory are focused on quantitative biomedical image processing and analysis. I am also interested in developing end-user biomedical software and building novel biomedical instruments, e.g., handheld devices that will allow noninvasive microscopic and tomographic optical imaging. This work will build on my previous research and expand into translational research that will directly support human health. My laboratory’s broad goal is to decipher meaningful information from anatomical structures and their pathologic conditions and connect them with molecular information to gain a better understanding of biological processes and disease. We focus on developing novel quantitative image processing and analysis methods, incorporating physical as well as statistical information of biological structures and their associated functional genomic information. Using statistical analysis, we have shown that our methods perform significantly better than existing ones. Existing methods in biomedicine typically do not employ both physical and statistical parameters associated with the imaging object and imaging system--and their environmental factors--while analyzing data. Thus, the results are often error-prone. By uniquely utilizing concrete physical and statistical modeling of the measurement data, our goal is to provide a more realistic profile and interpretation of complex biological systems and diseases. This, in turn, will provide new insights into diseases and improve disease diagnosis. My laboratory is woven strongly into the Department of Pathology and Anatomical Sciences’ innovative research and teaching directions that integrate anatomy, pathology and data analysis. Departmental faculty members participate in both graduate biomedical and medical programs; as part of that effort, I seek motivated students to work in my research group to focus on our novel research direction. I believe that teaching and research greatly complement each other, and I emphasize equally teaching in the classroom and guiding students in my research lab.
Multiple Sclerosis; Neurodegenerative disorders; Neuroimaging; Neurology; Neuroradiology - Radiology; Parkinson's; Radiological Physics; Radiology; Bioinformatics
Magnetic resonance imaging (MRI) is a unique technique for studying the human body since it is non-invasive, does not require ionizing radiation and offers a multiplicity of complementary tissue contrasts. My research seeks to explore the potential of MRI for clinical and pre-clinical imaging and to provide new and improved MRI technology. The goal of this endeavor is twofold: 1.) to contribute deeper insight into the etiology, pathogenesis and potential treatment of neurodegenerative diseases, and 2.) to give clinicians the ability to diagnose diseases earlier and monitor them more accurately. I am currently focusing on understanding MRI contrast mechanisms as well as on developing innovative imaging and reconstruction techniques that improve the sensitivity and specificity of MRI with respect to biophysical properties of brain tissue. Advancements in this field promise to have a substantial impact on our understanding of biophysical and morphological tissue alterations associated with neurological diseases and their treatment. We recently pioneered quantitative susceptibility mapping (QSM), a breakthrough in quantitative MRI. This technique allows for unique assessment of endogenous and exogenous magnetic particles in the human brain such as iron, calcium, myelin or contrast agents. The concept of QSM is fundamentally different from conventional MRI techniques as it involves solving for all imaging voxels simultaneously in large physically motivated equations, a so-called inverse problem. At the Buffalo Neuroimaging Analysis Center (BNAC), we use QSM to explore whether brain iron may serve as an early biomarker for diseases of the central nervous system such as multiple sclerosis and Parkinson’s disease. Other interesting applications of this technique we are investigating include differentiation between hemorrhages and calcifications, detection of demyelination and quantification of tissue oxygenation. I am fascinated by the synergies from combining physical expertise with high-level mathematical, numerical and engineering concepts to advance our understanding of the human brain. Consequently, my research activities are generally interdisciplinary and involve collaboration with clinicians, physicists, computer scientists, technicians and engineers. Student projects typically focus either on the application of techniques or on technical developments. Undergraduate, graduate and doctoral candidates from a variety of disciplines such as neuroscience, physics and mathematics work collaboratively in my lab.
Structural Biology; X-ray Crystallography; Bioinformatics; Proteins and metalloenzymes; Protein Function and Structure
Dr. Edward Snell is a Senior Scientist and Cheif Executive officer at the Hauptman-Woodward Medical Research Institute and faculty at the SUNY University at Buffalo Department of Structural Biology. He is a board member on the International Organization for Biological Crystallization, a member of the MacCHESS (The Macromolecular diffraction facility at Cornell High Energy Synchrotron Source) Advisory Committee and a member of the executive committee for the Stanford Synchrotron Radiation Lightsource users organization. He serves as a reviewer for multiple international Journals and both national and international funding agencies. He is on the American Crystallographic Association Communications Committee and chair-elect of the Biological Macromolecules Scientific Interest Group. His research group uses complementary techniques to extract structural and dynamic information from biological macromolecules. This research includes the development of crystallization methodology and the resulting analysis with an emphasis on high-energy light sources. Other techniques in use include Electron Paramagnetic Resonance and spectroscopy. He is experienced in solution scattering techniques, having organized and taught at both national and international meetings. The Snell laboratory research is supported by NIH, NSF, DoD, and NASA in addition to non-federal sources.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Gene therapy; Genome Integrity; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Signal Transduction; Stem Cells; Transcription and Translation
The long term mission of our laboratory, which I co-direct with Dr. Ewa Stachowiak, is to understand the principles governing molecular control of neural development, the implications for developmental- and aging-related diseases and the wide ranging effects on brain functions including behavior. The main achievement of our program has been the discovery of “Integrative Nuclear FGFR1 Signaling”, INFS a universal signaling mechanism which plays a novel integral role in cell development and complements other universal mechanisms such as mitotic cycle and pluripotency .Based on these revolutionary findings we have formulated a new theory called “Feed-Forward End-Gate Signaling” that explains how epigenetic factors either extracellular like neurotransmitters, hormonal or growth factors or intracellular signaling pathways control developmental gene programs and cellular development. This discovery is a product of our twenty-year multidisciplinary research that has been reported in several peer-reviewed papers in major journals including Proc. Natl. Acad. of Science (USA), Integrative Biology, Molecular Biology of the Cell, Journal of Cell Biology, Journal of Biological Chemistry, Journal of Physical Chemistry (etc.). In addition, we have applied this theory to analyze the etiology of neurodevelopmental /neurodegenerative disorders, and cancer in order to utilize it in new potential therapies. Towards these goals we have employed new technologies for an in vivo gene transfer, developed new transgenic mouse models for Schizophrenia and Parkinson-like diseases and established an interdisciplinary Molecular and Structural Neurobiology and Gene Therapy Program which has o engaged researchers from the different UB departments, other universities in the US as well as foreign institutions including Hannover Medical School (Germany), Gdansk Medical University, and Polish Academy of Science. Detailed research activities and future goals of our research program: 1. Molecular mechanisms controlling development of neural stem and related cells. In studying molecular mechanisms controlling development of neural stem and related cells we have established a novel universal signal transduction mechanism -Feed-Forward-And Gate network module that effects the differentiation of stem cells and neural progenitor cells. In the center of this module is the new gene-controlling mechanism "Integrative Nuclear Fibroblast Growth Factor Receptor-1 (FGFR1) Signaling" (INFS), which integrates diverse epigenetic signals and controls cell progression through ontogenic stages of proliferation, growth, and differentiation. We have shown that, Fibroblast Growth Factor Receptor-1 (FGFR1) a protein previously thought to be exclusively involved with transmembrane FGF signaling, resides in multiple subcellular compartments and is a multifactorial molecule that interacts with diverse cellular proteins In INFS, newly synthesized FGFR1 is released from the endoplasmic reticulum and translocates to the nucleus. In the nucleus, FGFR1 associates with nuclear matrix-attached centers of RNA transcription, interacts directly with transcriptional coactivators and kinases, activates transcription machinery and stimulates chromatin remodeling conducive of elevated gene activities. Our biophotonic experiments revealed that the gene activation by nuclear FGFR1 involves conversion of the immobile matrix-bound and the fast kinetic nucleoplasmic R1 into a slow kinetic chromatin binding population This conversion occurs through FGFR1’s interaction with the CBP and other nuclear proteins. The studies support a novel general mechanism in which gene activation is governed by FGFR1 protein movement and collisions with other proteins and nuclear structures. The INFS governs expression of developmentally regulated genes and plays a key role in the transition of proliferating neural stem cells into differentiating neurons development of glial cells, and can force neoplastic medulloblastoma and neuroblastoma cells to exit the cell cycle and enter a differentiation pathway and thus provides a new target for anti-cancer therapies. In our in vitro studies we are using different types of stem cells cultures, protein biochemistry, biophotonics analyses of protein mobility and interactions [Fluorescence Recovery after Photobleaching (FRAP), Fluorescence Loss In Photobleaching (FLIP), and Fluorescence Resonance Energy Transfer (FRET)] and diverse transcription systems to further elucidate the molecular circuits that control neural development. 2. Analyses of neural stem cell developmental mechanisms in vivo by direct gene transfer into the mammalian nervous system. An understanding of the mechanisms that control the transition of neural stem/progenitor cells (NS/PC) into functional neurons could potentially be used to recruit endogenously-produced NS/PC for neuronal replacement in a variety of neurological diseases. Using DNA-silica based nanoplexes and viral vectors we have shown that neuronogenesis can be effectively reinstated in the adult brain by genes engineered to target the Integrative Nuclear FGF Receptor-1 Signaling (INFS) pathway. Thus, targeting the INFS in brain stem cells via gene transfers or pharmacological activation may be used to induce selective neuronal differentiation, providing potentially revolutionizing treatment strategies of a broad range of neurological disorders. 3. Studies of brain development and neurodevelopmental diseases using transgenic mouse models. Our laboratory is also interested in the abnormal brain development affecting dopamine and other neurotransmitter neurons and its link to psychiatric diseases, including schizophrenia. Changes in FGF and its receptors FGFR1 have been found in the brains of schizophrenia and bipolar patients suggesting that impaired FGF signaling could underlie abnormal brain development and function associated with these disorders. Furthermore the INFS mechanism, integrates several pathways in which the schizophrenia-linked mutations have been reported. To test this hypothesis we engineered a new transgenic mouse model which results from hypoplastic development of DA neurons induced by a tyrosine kinase-deleted dominant negative mutant FGFR1(TK-) expressed in dopamine neurons. The structure and function of the brain’s DA neurons, serotonin neurons and other neuronal systems including cortical and hippocampal neurons are altered in TK- mice in a manner similar to that reported in patients with schizophrenia. Moreover, TK- mice express behavioral deficits that model schizophrenia-like positive symptoms (impaired sensory gaiting), negative symptoms (e.g. low social motivation), and impaired cognition ameliorated by typical or atypical antipsychotics. Supported by the grants from the pharmaceutical industry we are investigating new potential targets for anti-psychotic therapies using our preclinical FGFR1(TK-) transgenic model. Our future goals include in vivo gene therapy to verify whether neurodevelopmental pathologies may be reversed by targeting endogenous brain stem cells. Together with the other researchers of the SUNY Buffalo we have established Western New York Stem Cells Analysis Center in 2010 which includes Stem Cell Grafting and in vivo Analysis core which I direct. Together with Dr. E. Tzanakakis (UB Bioengineering Department) we have written book “ Stem cells- From Mechanisms to Technologies’ (World Scientific Publishing, 2011). Educational Activities and Teaching: I have participated together with the members of our neuroscience community in developing a new Graduate Program in Neuroscience at the SUNY, Buffalo. I am teaching neuroanatomy courses for dental students (ANA811) and for graduate students (NRS524). At present I participate in team-taught graduate courses in Neuroscience and Developmental Neuroscience (NRS 520, 521 and NRS 524). I am serving as a mentor for several undergraduate, graduate (masters and doctoral students) and postdoctoral fellows in the Neuroscience Program, Anatomy and Cell Biology Program and in the IGERT program in the Departments of Chemistry and Engineering. Additionally to mentoring master and Ph.D. students at the UB, I have helped to train graduate students in the University of Camerino (Italy) and Hannover Medical School (Germany). The works of our graduate students have been described in several publications.
Bioinformatics; Gene Expression; Genomics and proteomics
The recent development of high-throughput genomics technologies is revolutionizing many aspects of modern biology. However, the lack of computational algorithms and resources for analyzing massive data generated by these techniques has become a rate-limiting factor for scientific discoveries in biology research. In my laboratory, we study machine learning, data mining and bioinformatics and their applications to cancer informatics and metagenomics. Our work is based on solid mathematical and statistical theories. The main focus of our research is on developing advanced algorithms to help biologists keep pace with the unprecedented growth of genomics datasets available today and enable them to make full use of their massive, high-dimensional data for various biological enquiries. My research team is working on two major projects. The first is focused on metagenomics, currently funded by the National Institutes of Health (NIH), the National Science Foundation (NSF) and the Women’s Health Initiative. Our goal is to develop an integrated suite of computational and statistical algorithms to process millions or even hundreds of millions of microbial genome sequences to: 1) derive quantitative microbial signatures to characterize various infectious diseases, 2) interactively visualize the complex structure of a microbial community, 3) study microbe-microbe interactions and community dynamics and 4) identify novel species. We collaborate with researchers throughout the University at Buffalo, notably those in the School of Medicine and Biomedical Sciences, the School of Public Health and Health Professions and the College of Arts and Sciences. The second project focuses on cancer progression modeling. We use advanced computational algorithms to integrate clinical and genetics data from thousands of tumor and normal tissue samples to build a model of cancer progression. Delineating the disease dynamic process and identifying the molecular events that drive stepwise progression to malignancy would provide a wealth of new insights. Results of this work also would guide the development of improved cancer diagnostics, prognostics and targeted therapeutics. The bioinformatics algorithms and software developed in our lab have been used by more than 200 research institutes worldwide to process large, complex data sets that are core to a wide variety of biological and biomedical research.
Structural Biology; X-ray Crystallography; Bioinformatics; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Molecular and Cellular Biology; Protein Function and Structure; Proteins and metalloenzymes; Virology
The overarching goal of the Umland Lab is to use structural biology combined with biochemical, molecular biology, and genetics to explore important elements of infectious disease. The objective is to both extend the fundamental understanding of how microbial pathogens interact with their respective hosts and to identify new antimicrobial targets and new antimicrobial therapeutics. Two major projects on this theme are on going within the lab. In the first, unrecognized and underexploited potential antimicrobial targets within multi-, extreme, and pan-drug resistant gram-negative bacilli (GNB) are being identified and then characterized using the phenotype of in vivo essentiality. That is, our interest is in genes and their corresponding gene products that are essential for bacterial growth and survival during infection of a host (i.e., in vivo) rather than only essential under ideal laboratory growth conditions (e.g., rich laboratory media, absence of immune responses, etc.). The class of genes that are in vivo essential but not in vitro essential has largely been neglected as antimicrobial targets, and so represents a rich set for expanding target space in the urgent race to develop new antimicrobials. The second project is focused upon identifying and characterizing virus protein - host protein interactions. Viruses encode a highly limited set of functionality, and therefore rely on subverting cellular machinery. This high jacking of cellular functions for the benefit of the virus often involved virus-host protein-protein interactions (PPIs). Study of these virus-host PPIs reveals both the mechanisms by which viruses co-opt cellular functions and potential new antiviral targets recalcitrant to the development of drug resistance. An additional rationale for studying virus-host PPIs is to understand virus evolution with respect to PPI involvement in virulence, pathogenesis, and host tropism. In conjunction with both of these projects, the Umland Lab is using structurally enabled fragment-based lead discovery (FBLD) methods to identify small molecules with potential to be developed into antimicrobial therapeutics.