Cell growth, differentiation and development; Cytoskeleton and cell motility; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Gene Expression; Signal Transduction; Cell Cycle
I am a cell biologist and bioengineer, and my primary research focuses on the rapidly growing area of cell mechanics and mechanotransduction: the role that mechanical forces play in regulating cellular function from healthy to diseased phenotypes. (1) Cardiovascular Biology, Mechanics and Disease: Funding source: American Heart Association (7/1/2018–6/30/2021; PI) Cardiovascular disease (CVD) is the main cause of death globally. Arterial stiffness is associated with many CVD. The molecular mechanisms governing arterial stiffening and the phenotypic changes in vascular smooth muscle cells (VSMCs) associated with the stiffening process are key areas in cardiovascular biology, mechanics and disease. Evidence suggests that arterial stiffening can drive aberrant migration and proliferation of VSMCs within the vessel wall. Yet, the underlying mechanisms regulating vascular stiffening and the molecular changes within VSMCs associated with the stiffening process remain unclear. While medications reduce hypertension, none specifically target pathways directly related to arterial stiffness. The overall goal of work in my lab is to address this gap in our understanding by investigating how changes in arterial stiffness affect VSMC function and fundamentally contribute to the progression of CVD. This study also addresses an important concept in vascular tissue remodeling (the interaction between extracellular matrix stiffness and VSMC behavior). Methodologically, my lab use a novel approach to dissect the molecular mechanism in VSMCs: My lab combines methods for manipulating and measuring tissue and cell stiffness using atomic force microscopy and traction force microscopy for simultaneously modulating substrate stiffness and measuring contraction force by culturing cells on a compliant substrate that mimics in vivo mechanical environments of the VSMCs. (2) Smooth Muscle Cell (and Cancer Cell) Heterogeneity: Highly heterogeneous responses of VSMCs to arterial stiffness or CVD make it difficult to dissect underlying molecular mechanisms. To overcome this, my lab integrates Mechanobiology, Vascular Cell Biology, and Machine Learning to manipulate stiffness and assess responses with unique precision. Machine learning is used to deconvolve inter- and intra-cellular heterogeneity and identify specific subcellular traits that correlate with stiffness and VSMC behavior. My lab also applies Machine Learning approaches to identify specific breast cancer cell behaviors that respond to different stiffness conditions. (3) Optogenetics and Biophotonics in Stem Cell Biology: Funding source: National Science Foundation (8/1/2017–7/31/2020; co-PI) Major breakthroughs in the field of genomics, embryonic stem cell biology, optogenetics and biophotonics are enabling the control and monitoring of biological processes through light. Additional research in my laboratory focuses on developing a nanophotonic platform able to activate/inactivate gene expression and, thus, control stem cell differentiation in neuronal cells, by means of light-controlled protein-protein interactions. More specifically, the light-controlled molecular toggle-switch based on Plant Phytochrome B and transcription factor Pif6 will be utilized to control the nuclear fibroblast growth factor receptor-1, which is a master regulator of stem cell differentiation. Open Positions: The Bae lab is currently accepting graduate students through the Pathology Masters program (or other programs) as well as motivated undergraduates. For Graduate Students: I am looking for one or two graduate (MS) students who understand my research interests, have read my previous publications, and have their own (crazy!!!) ideas as to where my research efforts should be directed. All graduate students are required to complete and submit internationally recognized Journal article(s) before graduation from my lab. A Masters thesis should generate at least one first author publication. For Undergraduate Students: I encourage all UB undergraduates (with GPA 3.0 or higher) to get "hands on" experimental training in the sciences. An undergraduate research project tends to be part of a larger whole, but I make sure to include credit for students work in presentations and publications.
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Instructions controlling cellular functions are contained within DNA that is wrapped and packaged around proteins into chromatin. Chromatin can be modified in response to the environment and these modifications can be passed onto their daughter cells. These modifications act as a cellular memory and are known as epigenetic modifications. Changes in epigenetic modifications are essential players in many disease pathways including: cancer, diabetes, obesity, and autism. Dr. Buck’s research is focused on uncovering how epigenetic changes redirect regulatory proteins and how regulatory proteins read epigenetic modifications. Dr. Buck’s laboratory uses multiple model systems to uncover fundamental biological principles which are subsequently translated to the study of human disease. Epigenomics and Cancer Epigenetic alterations have been associated with cancer-specific expression differences in development of human tumors. The ability to recognize and detect the progression of epigenetic events occurring during tumorigenesis is critical to developing strategies for therapeutic intervention. Key epigenetic alterations, leading to silencing or activation, are associated with changes in nucleosome occupancy. We use chromatin assays (FAIRE-seq, ATAC-seq, MNase-seq, and ChIP-seq) to examine cancer epigenomes from patient samples and cell line models. Transcription factor binding specificity to chromatin. To understand normal developmental processes and disease manifestation and progression we must understand the mechanisms regulating the essential first step of gene activation, transcription factor binding at regulatory regions. Using the developmental transcription factor TP63 we have begun to uncover the rules dictating p63 binding to chromatin. Our findings demonstrated that p63 functions has a pioneer transcription factor that can target it bindings site in closed inaccessible genomic locations. Current in vitro and in vivo studies are beginning to define the how nucleosome position and histone modifications regulate p63 binding. Microbiota in human health Our bodies are populated by a diverse and complex population of thousands of microbes, mostly bacteria, but also viruses, fungi and archaea, termed the human microbiota. This co-inhabiting microbial ecosystem has been associated with various human disease including colon cancer, diabetes, periodontal disease, and others. To understand how the microbiota is affecting human health we are participating in a large epidemiological study examining human oral microbiota samples. We have developed robust and reproducible high-throughput approaches to examine thousands of samples and we are currently defining causual relationships between the microbiota and human health.
Cardiology; Cardiovascular Disease; Apoptosis and cell death; Cardiac pharmacology; Gene therapy; Genomics and proteomics; Molecular Basis of Disease; Stem Cells
As chief of the Division of Cardiovascular Medicine at UB, I am responsible for the clinical, teaching and research programs related to adult patients with heart disease. I care for patients at the UBMD Internal Medicine practice group in Amherst, the Gates Vascular Institute (GVI) of Buffalo General Medical Center (BGMC) and the Buffalo VA Medical Center (VAMC). My clinical areas of expertise are in diagnosing and caring for patients with coronary artery disease and heart failure. My research group conducts translational studies directed at advancing our mechanistic understanding of cardiac pathophysiology as well as developing new diagnostic and therapeutic approaches for the management of patients with chronic ischemic heart disease. Our ongoing areas of preclinical investigation apply proteomic approaches to identify intrinsic adaptive responses of the heart to ischemia and studies examining the ability of intracoronary stem cell therapies to stimulate endogenous cardiomyocyte proliferation and improve heart function. We also conduct basic and patient-oriented research to understand how reversible ischemia modifies the cellular composition and sympathetic innervation of the heart to help develop new approaches to identify patients at risk of sudden cardiac arrest from ventricular fibrillation. In addition to my laboratory investigation, I serve as the deputy director of the UB Clinical and Translational Research Center (CTRC) and the director of the UB Translational Imaging Center. The Translational Imaging Center offers researchers opportunities to perform multimodality research imaging using PET molecular imaging, high-field magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Our overall goal is to use advanced cardiac imaging to translate new applications between the bench and bedside in order to identify new imaging biomarkers of pathophysiological processes such as chronic myocardial ischemia and cardiac arrhythmogenesis. I am engaged in the cardiology profession at national and international levels, including as former president of the Association of Professors of Cardiology.
Allergy and Immunology; Medical Microbiology; Infectious Disease; Microbiology; Genomics and proteomics; Immunology; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Gene Expression; Signal Transduction; Protein Function and Structure; Bacterial Pathogenesis
Research efforts in my laboratory are focused in the fields of immunology and bacterial pathogenesis, two diverse fields of biomedical research for which I have two separate research groups. Projects in both fields are performed by undergraduates, doctoral and master’s degree students, postdoctoral fellows and senior research associates. One major focus of my laboratory is studying the regulation of mucosal immune responses. We investigate the cellular and molecular events by which Type II heat-labile enterotoxins (HLTs), produced by certain strains of Escherichia coli, modulate immune responses. We have demonstrated that LT-Ilia, LT-IIb and LT-IIc, when co-administered with an antigen, have the capacity to enhance antibody and cellular immune responses to that antigen. Using a variety of immunological and cellular technologies, including flow cytometry, fluorescence resonance energy transfer (FRET) detection, cytokine multiplex analysis, mutagenesis, quantitative Reverse Transcription PCR (qRT-PCR), RNA-sequencing (RNA-Seq) and a variety of transgenic mice, we are investigating the mechanisms by which these immunomodulators productively interact with various immunocompetent cells (T cells, B cells, dendritic cells, macrophages) to induce or suppress cytokine production, costimulatory ligand expression and cellular proliferation. A practical outgrowth of these experiments is the potential to engineer novel recombinant vaccines by genetically fusing antigens from different pathogens to the enterotoxins. Recent experiments have shown that these HLT are lethal for triple-negative breast cancer cells, which has opened a new area of oncological research for the lab. A second focus of my laboratory is to investigate the molecular mechanisms by which adherent-invasive Escherichia coli (AIEC) induce, exacerbate or prolong the symptoms of inflammatory bowel disease (IBD) and Crohn’s disease, two acute and chronic inflammatory diseases of the human gut. In vitro, AIEC strains invade into the cytoplasm of several epithelial cell lines. Using recombinant screening methods and RNA-Seq technologies, we are identifying the genes of AIEC that are required to attach and to invade gut cells.
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.
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.
Genomics and proteomics; Protein Function and Structure; Proteins and metalloenzymes
The Malkowski Laboratory is focused on understanding the structure and function of integral membrane enzymes involved in the conversion of lipid precursors into potent bioactive signaling molecules. We utilize a myriad of methods and techniques to characterize these enzymes, including X-ray crystallography, electron spin resonance spectroscopy, protein chemistry, biochemistry, molecular biology, cell biology, and kinetics.
Pulmonary & Critical Care Medicine; Bioinformatics; Gene Expression; Genomics and proteomics; Immunology; Protein Function and Structure
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, interstitial lung disease, pleural disease, pulmonary hypertension 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, pleural disease, interstitial lung disease, pulmonary hypertension and lung cancer, at the UBMD practice location at Conventus. As a member of the UBMD pulmonary division I provide inpatient pulmonary consultation at both BGMC and Roswell Park Cancer Institute. Currently I am focusing on the analysis of Big Data in medical/healthcare fields. I am particularly focused on the application of drug repurposing in translation and clinic research. Additionally, 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. My collaborators include the Division of Allergy and Immunology. We endeavor 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 patient with pulmonary disease and the critically ill patient.
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 combinatorial approach encompassing genetics, molecular biology, genomics, single cell analysis and bioinformatics.
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.
Eukaryotic Pathogenesis; Gene Expression; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; RNA
Trypanosoma brucei is a eukaryotic pathogen that causes human African trypanosomiasis, a disease that is invariably fatal if not treated. Essential and novel processes in this parasite may serve as starting platforms for new chemotherapeutics, which are urgently needed. Our laboratory combines biochemical, genetic, genomic and proteomic approaches toward understanding gene regulation and protein modification in this pathogenic eukaryote. One focus in my laboratory is RNA editing, a novel mechanism for regulating mitochondrial gene expression in which sequence information is added to mRNAs after transcription by specific insertion and deletion of uridine residues. RNA editing is essential for creating translatable open reading frames (ORFs). We are performing functional and biochemical characterization of the large, dynamic RNA-protein complex termed MRB1, which coordinates multiple aspects of the RNA editing process. A second focus is on regulating RNA stability and translational control in T. brucei, which constitute the major methods of gene regulation in this organism. We identified an RNA binding protein, DRBD18, that impacts the stabilities of hundreds of mRNAs. Our data support a model in which posttranslational modification of DRBD18 by arginine methylation acts as a switch to change DRBD18 from an mRNA destabilizer to an mRNA stabilizer by regulating specific protein-protein and protein-RNA interactions. We are testing this model in vitro and in vivo using reporter assays, in vivo protein-RNA cross-linking and protein-protein interaction assays. A third focus is on understanding the mechanisms by which protein arginine methylation modulates trypanosome biology. We performed a global proteomic analysis of the arginine methylome of T. brucei, identifying >1100 methylproteins spanning most cellular compartments and a wide array of functional classes. We are now analyzing novel mechanisms of protein arginine methyltransferase regulation and defining the physiological and molecular functions of arginine methylmarks on selected proteins. I foster a collaborative and flexible laboratory environment, and I encourage my students to explore the research topics that interest them.
Gene therapy; Genomics and proteomics; Immunology; Infectious Disease; Neurobiology; Neuropharmacology; Viral Pathogenesis; Virology
As a postdoctoral fellowship in the Division of Allergy, Immunology & Rheumatology at University at Buffalo I received a NIDA funded National Research Service Award (NRSA) F32 to study the mechanisms of cocaine-induced HIV-1 infection in astrocytes. This was a two year fellowship award ($99,224). I received several Young Investigator Travel Awards to attend and present my research at national conferences including the Society for NeuroImmune Pharmacology, the College on Problems of Drug Dependence and the International Society for NeuroVirology. I was the first to demonstrate that cocaine enhances the replication of HIV in astrocytes, specialized glial cells in the central nervous system. During this time I was first author on 3 publications and contributed as a co-author on 6 publications in internationally recognized, peer reviewed journals including the Journal of Immunology, Brain Research and Biochimica et Biophysica Acta. As a Research Assistant Professor in the Division of Immunology I was funded through a NIDA Mentored Research Scientist Development Award (K01) award to investigate targeted nanoparticles for gene silencing in the context of HIV and drug abuse. This K01, was a five year award, $785000 that allowed for advanced training in nanotechnology and immunology. I applied this new expertise in nanotechnology to the development of innovative methods to control HIV-1 infections, particularly those associated with methamphetamine abuse. I was an invited panel speaker at the International Symposium on NeuroVirology and the American College of Neuropsychopharmacology. During this time, I published approximately 30 peer-reviewed publications in internationally recognized, peer-reviewed journals, including journals such as the Journal of Immunology, Brain Research, and the Journal of Pharmacology Experimental Therapeutics. Six as first author, 1 as senior author and 23 as a co-author. Presently, I am a Associate Professor and Proposal Development Officer in the Department of Medicine at University at Buffalo where I continue to develop my research in drug delivery methods. I am currently investigating exosomes as potential delivery vehicles. Exosomes are one of several types of membrane vesicles known to be secreted by cells including microvesicles, apoptotic bodies, or exosome-like vesicles. Exosomes, unlike synthetic nanoparticles, are released from host cells and have the potential to be novel nanoparticle therapeutic carriers I have recently been invited to be a panel speaker at the American Society of Nanomedicine and the American Society of Gene & Cell Therapy conferences. I have been a principal investigator and co-instigator on NIH funded projects studying multimodal nanoparticles for targeted drug delivery and immunotherapy in Tuberculosis and HIV and a co-investigator on a NYS Empire Clinical Research Investigator Program (ECRIP) to develop a Center for Nanomedicine at UB and Kaleida Health. I have had over eight years of NIH supported funding.
Genomics and proteomics; Molecular and Cellular Biology; Regulation of metabolism; Toxicology and Xenobiotics
Dr. David Shubert has been at the University at Buffalo since 2006. He received is B.S in Pharmacy from Duquesne University and a Ph.D from the University at Buffalo. His research interests include the mechanism by which environmental chemicals initiate and promote cancer. He is the Assistant Dean for Biomedical Undergraduate Education and teaches pharmacology, toxicology and cardiovascular physiology. Dr. Shubert accepts undergraduate students interested in pursuing research in his areas of interest. He is an active member of the Society of Toxciology.
Genomics and proteomics; Neurobiology; Neurodegenerative disorders
My lab investigates the molecular control of cell fate and homeostasis of resident stem and progenitor cells in the human brain. Using a combination of multicolor cell sorting techniques and whole genome analysis, we are characterizing the signaling pathways which regulate the formation and fate of human oligodendrocyte progenitor cells. We are testing the functional significance of these pathways using both pharmacological and viral methods in culture and animal-based models of myelination and demyelination.
Genomics and proteomics; Molecular and Cellular Biology; Gene Expression
My laboratory is interested in understanding the transcriptional control mechanisms that dictate epithelial cell development and differentiation. Specifically, we seek to understand the functional role of a p53-family member, p63 and Ets family of proteins in epithelial cells such as those of the skin and mammary glands. Towards this end, we have developed and characterized transgenic mice in which the normal expression pattern of these crucial factors is altered by both gain-of-function (Tet-inducible transgenic system) and loss-of-function (knockout) experiments. Our broad objectives are to elucidate the molecular mechanism by which transcription factors such as p63 and Ets proteins regulate their target genes and how such regulation of specific pathways dictate cell fate, development and differentiation. We utilize broad biochemical and genetic approaches, cell culture systems and state of the art genome-wide interrogation techniques to answer questions about differentiation of progenitor/stem populations and to examine molecular consequences of altered expression of transcription factors. These studies will not only help better understand the normal physiological processes but also lead to novel mechanistic insights into the pathophysiology of wide range of disease including cancer.
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.