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.
Reproductive Endocrinology; Apoptosis and cell death; Cell growth, differentiation and development; Endocrinology; Gene Expression; Molecular genetics; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
My research focuses on developing, promoting, and evaluating effective means of pharmacology instruction at the undergraduate, graduate, professional, and interprofessional levels. Developing a competency-based curriculum in pharmacology for students at all levels, I have incorporated specific instructional methods into existing core courses that has in effect taken a sometimes intimidating subject like pharmacology and presented it to students in manageable way. Studies of the effectiveness of these methods are conducted in collaboration with the American Society of Pharmacology and Experimental Therapeutics (ASPET) and its Division of Pharmacology Education of which I am a recently appointed Fellow. Specific instructional methods in the study include: patient case presentations by dental students which utilize rubric descriptors of performance quality; Pharm Fridays with second year medical students incorporating organized lists of pertinent drugs to recognize, student-oriented learning objectives, pharmacology study guides, and active participation clicker sessions with relevant board-style pharmacology questions; development of performance-based pharmacology questions within the multidisciplinary objective structured clinical exam (OSCE) taken by all DDS candidates; and video clip presentations within classes demonstrating pertinent pharmacology topics such as medical sedation, use of emergency drugs in the clinic, and alternative means for pain management with interviews of clinical experts. These and other instructional methods in the study are highly rated by students and proven effective by outcomes on standardized exams.
Oncology; Cell Cycle; Cell growth, differentiation and development; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction; Transcription and Translation
Protein phosphorylation is an essential mechanism by which intercellular signals regulate specific intracellular events. Protein kinases, the enzymes catalyzing protein phosphorylation reactions, represent a major superfamily of genes, collectively representing 2% of the protein coding potential of the human genome. Current projects in Dr. Edelman‘s lab are devoted to the role of protein kinases in prostate and ovarian cancer. These projects utilize a wide range of techniques and involve, collaboration with investigators at Roswell Park Cancer Institute to develop protein kinase-targeted therapies for both types of cancer.
Pediatric Surgery; Pediatric Urology; Pulmonary Disease; Surgery; Surgical Critical Care - Surgery; Thoracic Surgery; Surgery - Trauma; Surgery - Laparoscopic; Prenatal Diagnosis; Fetal Surgery; Miniature Access Surgery; Cell growth, differentiation and development; Molecular Basis of Disease
-To be a recognized leader in academic pediatric surgery (clinical surgery, clinical/basic science research, teaching and administration), -To build a state of the art surgical department, divisions, and programs congruent withthe mission goals, and needs of institutions (university, hospital, other departments), patients and their families and faculty (full time and volunteer) -To create the requiste environment for students, residents, and faculty to optimize career development -To maintain a busy clinical pratice of open and miniature access surgery for fetuses, infants, children -To cross train students (MD, RN, DDS, Phar D.,MPH, Basic Science, Residents and Fellows(all specialties), Faculty (all Health Science Schools),and Community Healthcare Professionals in the requisite MBA Skill Sets, Entrepreneurism, and Big Data analysis to optimize their professional development, careers and their patients‘ outcomes in this complicated and ever changing Healthcare environment -To be actively involved in teaching and practicing Interprofessional Care (IPC) and Interprofessional Education (IPE) -To continue to train and mentor academic gerneral surgeons -To continue to train and mentor academic pediatric surgeons -To continue to teach and mentor students at various levels -To continue laboratory and clinical incestifations in the following areas: lung development, congenital diaphragmatic hernia, fetal physiology, birth defects, prenatal diagnosis of surgical problems, fetal surgery, the genetic aspects of surgical disease, fetal frowth factors, the physiology miniature access surgery, surgical robotics, ECMO, trauma, the education process for students, residents, and fellows virtual reality, surgical simulation, telelmedicine, telesurgery, teleconferencing, telementoring, and computer applications in medicein -To continue research and development with corporate biomedical parners -To continue to advocate for children and children‘s health care
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.
Mucociliiary Transport; Cell growth, differentiation and development; Cytoskeleton and cell motility; Molecular and Cellular Biology; Signal Transduction
Our lab is involved in two major projects: 1) Cell motility research – mucociliary transport. We have developed a series of real “models” or simplifications of the respiratory mucociliary epithelium (primary cultures, isolated epithelial sheets, isolated ciliated cells, demembranated and MgATP-reactivated cell models, and isolated, demembranated and reactivated ciliary axonemes) that allow one to study mucociliary transport at number of levels of organization. We have studied these models using biochemical methods, stroboscopic imaging, high speed image analysis, and EM to analyze the control of the beat frequency, waveform and coordination of respiratory cilia. We have developed correlative LM/EM methods and correlative live/immunofluorescence methods for this purpose. These studies have import for 1) detecting and understanding abnormal parameters of ciliary function, as in primary ciliary diskinesis (PCD) 2) for the testing of exogenous agents (drugs, environmental agents, etc.) on mucociliary transport. 2) Along with 4 other UB labs in Chemistry and Engineering, plus 1 lab in Head and Neck Surgery Dept. at Roswell Park, our lab is involved in an interdisciplinary project to develop a “high tech bandage” that is doped with tissue specific growth factors and cytokines that can be released with full activity and at known rates to stimulate wound healing in scrape and burn types of acute (and potentially, chronic) injuries. These agents are selected to promote: a) the motogenic and mitogenic activity of epithelia and b) blood vessel formation. Our lab specifically is responsible for the in-vitro testing of doped membranes for their ability to promote wound closure (re-epithelialization of 9 mm wounds) in a human epidermal cell line by image analysis of wound closure kinetics and cell division and cell death rates. We also are responsible for the in-vivo testing of such membranes in animals using a porcine burn model to assay inflammation, epithelial closure rates, blood vessel formation, and inflammation. As a faculty member and Co-Director of one of the oldest biological imaging courses in the U.S. (Optical Microscopy and Imaging in the Biomedical Sciences Course, Marine Biology Laboratory, Woods Hole, MA) my lab frequently is asked to help other researchers with digital imaging problems and has contributed computerized digital image analyses in a number of scientific publications.
Ear, Nose, Throat (Otolaryngology); Oncology; Plastic Surgery for Head (Ear, Nose,Throat); Cell growth, differentiation and development
Wesley L. Hicks Jr., M.D., is chair of the Head and Neck/Plastic & Reconstructive Surgery Program at Roswell Park Cancer Institute in Buffalo, NY. Dr. Hicks is Board Certified by the National Board of Medical Examiners and the American Board of Otolaryngology. He is also a tenured Professor of Otolaryngology/Head and Neck Surgery and Professor of Neurosurgery and Bioengineering at the University at Buffalo School of Medicine and Biomedical Sciences. His research interests focus on tissue engineering, wound healing and mechanisms involved in wound repair. His laboratory is studying novel work in bioengineered devices for enhanced wound repair, as well as cellular microenvironment effecting tissue remodeling and repair. Dr. Hicks was recently named one of the nation’s Top Cancer Doctors by Newsweek magazine and is a recipient of the American Academy of Otolaryngology’s Head and Neck Surgery Honor Award. He was also selected as one of the top 100 physicians in the nation by Black Enterprise magazine. He earned his dental degree at Meharry Medical College and his medical degree at the University at Buffalo School of Medicine and Biomedical Sciences. He completed his residency in Otolaryngology, Head & Neck Surgery at the Manhattan Eye, Ear and Throat Hospital, New York Hospital — Cornell Medical Center, Memorial Sloan-Kettering Cancer Center, New York, NY, and his Fellowship in Head & Neck Surgery at Stanford University Medical Center, Palo Alto, CA. Dr. Hicks is a member of a number of professional organizations, including the National Medical Association, the Triologic Society, the American Medical Association, the American Academy of Otolaryngology/Head & Neck Surgery, the American College of Surgeons, the American Head & Neck Society, and the Society of Black Academic Surgeons. He was a Senior Examiner for the American Board of Otolaryngology. His community affiliations include board memberships on the Board of Directors of HealthNow Inc./BlueCross BlueShield of New York State, the Urban League, the advisory board of First Niagara Bank and WBFO — the National Public Radio (NPR) affiliate. He also is a Commissioner of the Niagara Frontier Transportation Authority. Dr. Hicks has authored or co-authored more than 200 journal publications, book chapters and abstracts, and has been issued a number of patents related to his interest in tissue engineering and wound healing.
Neonatal-Perinatal Medicine; Neonatology; Pediatrics; Cell growth, differentiation and development; Molecular and Cellular Biology; Cell Cycle
As a neonatologist working in a neonatal intensive care unit (NICU), I care for the sickest and most premature infants. At the Oishei Children’s Hospital and Millard Fillmore Suburban Hospital, I collaborate with fellows, residents, medical students, nurse practitioners, nurses — and other health care professionals involved in the care of infants in the NICU — to help these fragile infants overcome severe challenges to grow and thrive. My research is focused on improving the quality of life of newborns. My studies in the area of resuscitation and pulmonary hypertension are nationally recognized. I operate one of the few centers in the country that includes a newborn lamb model with which to conduct research in the areas of resuscitation, delayed cord clamping and asphyxia. I have done extensive study in hypertension in term and premature neonates, resuscitation (relating to heart rate and oxygen exposure) and long-term effects of hyperoxia and bronchopulmonary dysplasia. My upbringing in India has given me a deep appreciation for global health issues relating to maternal and child health. That has spurred me to try to develop low-cost technologies to improve neonatal and child health in developing countries, with an emphasis on resuscitation and birth asphyxia. I mentor fellows and help them learn the skills and techniques they need to be successful neonatologists, either in an academic setting or in private practice. I utilize the flipped classroom, delivering instruction online outside of class and moving “homework” into the classroom. I provide fellows with the freedom and independence to succeed by offering opportunities to learn and practice technical skills and by guiding fellows’ growth with timely feedback. I have more than 50 publications to my credit, and I make it my business to help fellows get their own research published. My guidance helps fellows give successful presentations at regional and national conferences. In fact, my trainees have received multiple awards for their research presentations at the Eastern Society for Pediatric Research meetings over the years. I am committed to my fellows’ success as the next generation of compassionate, competent neonatologists.
Cardiology; Cardiovascular Disease; Cell growth, differentiation and development; Gene Expression; Molecular and Cellular Biology; Signal Transduction; Stem Cells
As a general cardiologist, I diagnose and treat a wide range of problems that affect the heart and blood vessels, including but not limited to coronary artery disease, valvular heart disease, heart failure, diseases of the myocardium and pericardium, cardiac arrhythmias, conduction disorders and syncope. I attend on the inpatient Coronary Care ICU (CCU), Cardiac Step-down Unit, and Cardiology Consult service at Buffalo General Medical Center as well as see patients in my outpatient clinic. In addition to treating pre-existing cardiac conditions, I also believe in strong preventive care and addressing modifiable risk factors for coronary disease. I take time to get to know my patients, and I talk with them about measures they can take to reduce their risk for cardiovascular disease and improve their health. As a clinician-scientist, I have a special interest in developing new stem cell based treatments for heart disease. My research is focused on understanding what stem cell secreted factors are responsible for improved heart function, what their targets are and how these can be modulated to develop new cell-free therapies that can help patients with a wide spectrum of coronary disease and heart failure. I welcome medical students, graduate students, residents and fellows to conduct research with me in my lab. As a native Buffalonian, I am honored to partner with the patients in our community to help improve their heart health and cardiac knowledge base. I am equally excited to be involved in shaping the next generation of physicians through the teaching I conduct at the medical student, resident and fellow level.
Apoptosis and cell death; Cell growth, differentiation and development; Cytoskeleton and cell motility; Immunology; Signal Transduction; Stem Cells
My independent research at The University at Buffalo focuses on targeting the mammary gland microenvironment by evaluating cellular and tissue responses during specific developmental windows of mammary gland remodeling including puberty, the period of hormonal withdrawal during estrous cycling, or post-lactational involution. My choice to focus on discrete times of development for chemopreventive intervention, rather than long-term (and often life-time) intervention, represents a unique approach of short-term exposure at critical points of mammary gland development. Our goal is to allow women to bypass the need for lifelong compliance to a chemopreventive diet or drug regimen in order to attain lifelong protection against breast cancer. Developmentally targeted dietary interventions being investigated in our lab include continuous administration of oral contraceptives, dietary exposure to conjugated linoleic acid, and ethanol.
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; 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.
Cell growth, differentiation and development; Cytoskeleton and cell motility; Stem Cells
Development of regenerative therapeutics involves understanding and application of molecular, cellular and tissue engineering principles. Integrated strategies include biomaterials, therapeutic molecules and stem cells to create bioengineered systems for regenerative medicine. Therefore, understanding fundamental interactions between different components and utilizing these concepts will provide tools to engineer tissue regeneration and develop treatment options for diseases. The translational aspect of regenerative medicine depends on proper integration of engineering and medicine. This hierarchical roadmap is tissue or disease specific and thus requires step-wise approaches. Our current goals are to develop strategies for therapeutic angiogenesis, soft and elastic tissue regeneration and delivery of drugs. We are interested to integrate the different components for effective therapeutic strategies
Cell growth, differentiation and development; DNA Replication, Recombination and Repair; Gene Expression; Molecular and Cellular Biology; Proteins and metalloenzymes; Signal Transduction; Transcription and Translation
The main goal of my research group is to understand the role of N-terminal methylation on human development and disease. I identified the first eukaryotic N-terminal methyltransferases, NRMT1 and NRMT2, and am now working to identify how these enzymes and this new type of methylation affect cancer development and ageing. Our laboratory has shown that NRMT1 functions as a tumor suppressor in mammary glands, and its loss sensitizes breast cancer cells to DNA damaging chemotherapeutics. We have also created the first NRMT1 knockout mouse and shown it to have developmental defects, as well as, exhibit phenotypes of premature ageing. Currently, we are working to understand the exact biochemical pathways that lead from loss of N-terminal methylation to these phenotypes. We are also studying how post-translational modifications on the N-terminus of proteins may interact and dictate protein function, similar to the post-translational modifications found on histone tails.
Cell growth, differentiation and development; Gene Expression; Molecular and Cellular Biology; Neurobiology; Signal Transduction
The long term mission of my research has been to understand developmental and regenerative processes within the mammalian CNS. Towards these goals I have employed stereological and microscopic imaging techniques, stem cell cultures and in vivo models to analyze brain development, regenerative capacity, etiology of neurodevelopmental and neurodegenerative diseases. I have established a quantitative Neuroanatomy Stereology laboratory within a multi-disciplinary Molecular and Structural Neurobiology and Gene Therapy Program. Current projects: Developmental disorder- Schizophrenia The studies that I have been engaged in the last several years have addressed fundamental aspects of organismal development, their pathological disruptions and their targeting for regenerative medicine. With the advent of multicellular organisms, mechanisms emerged that imposed new controls which limited the natural propensity of organisms composed of single cells to proliferate, and to invade new locales, which ultimately results in the formation of tissues and organs. How such an immense task is accomplished has been largely unknown. Our collaborative studies have revealed a pan-ontogenic gene mechanism, Integrative Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1) Signaling (INFS), which mediates global gene programing through the nuclear form of the FGFR1 receptor (nFGFR1) and its partner CREB Binding Protein, so as to assimilate signals from diverse signaling pathways. My work, which has contributed to these findings, has been focused on the role of INFS in cellular development. I have shown that INFS is central to the development of neural cells and that pluripotent ESC and multipotent NPCs can be programmed to exit from their cycles of self-renewal, and to undergo neuronal differentiation simply by transfecting a single protein, nFGFR1. Using viral and novel, nanotechnology based gene transfers, I have demonstrated that it is possible to reactivate developmental neurogenesis in adult brain by overexpressing nFGFR1 in brain stem/progenitor cells. We have shown that similar effects can be produced by small molecules that activate the INFS. These findings may revolutionize treatments of abnormal brain development, injury and neurodegenerative diseases by targeting INFS to reactivate brain neurogenesis. Schizophrenia (SZ) has been linked to the abnormal development of multiple neuronal systems, and to changes in genes within diverse ontogenic networks. Genetic studies have established a link between FGFs and nFGFR1 with these networks and SZ. nFGFR1 integrates signals from diverse SZ linked genes (>200 identified) and pathways[2-6] and controls developmental gene networks. By manipulating nFGFR1 function in the brain of transgenic mice I have established a model that mimics important characteristics of human schizophrenia: including its neurodevelopmental origin, the hypoplasia of DA neurons, increased numbers of immature neurons in cortex and hippocampus, disruption of brain cortical layers and connections, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder, and their correction by typical and atypical antipsychotics[6, 7]. To understand how SZ affects neural development, I have begun to generate induced pluripotent stem cells (iPSCs) using fibroblast of SZ patients with different genetic backgrounds. In my studies I employ 3-dimensional cultures of iPSCs, co-developmental grafting of the iPSCs neural progeny into murine brain, FISH (Fluorescent In Situ Hybridization), gene transfer and quantitative stereological analyses. I am testing how genomic dysregulation affects the developmental potential of schizophrenia NPCs (formation of 3D cortical organoids, in vivo development of grafted iPSCs) which may be normalized by correcting nFGFR1 and miRNA functions. In summary, my studies are aimed to develop to new treatments for Schizophrenia and other neurodevelopmental disorders including potential preventive therapies. Effect of maternal diet and metabolic deficits on brain development (collaboration with Dr. Mulchand Patel, Department of Biochemistry, UB) Approximately 36% of the adults in the US are classified as obese. Available evidence from epidemiological and animal studies indicate that altered nutritional experiences early in life can affect the development of obesity and associated metabolic diseases in adulthood and subsequently in the offspring of these people. Furthermore, there is an increased risk for mental health disorders that is associated with these conditions. Our studies show that an altered maternal environment in female rats produced by consuming a high fat (HF) or high sugar diet (HS) negatively impacts the development of brain stem cells and fetal brain circuitry in the offspring[8, 9]. Increased numbers of immature, underdeveloped neurons are found in the hypothalamus, which controls feeding behavior. Similar changes are found in areas of the cerebral cortex involved in other diverse behavioral functions. These changes reveal an alarming predisposition for neurodevelopmental abnormalities in the offspring of obese female rats. Blast induced brain injury and regeneration (collaboration with Dr. Richard Salvi, Department of Communicative Disorders and Sciences, UB) Sound blast induced brain injury is a major concern in military exposure to excessive noise. In mice exposed to the sound blast we found marked loss of myelinated fibers and neuronal apoptosis in brain cortex. These degenerative changes were accompanied by increased proliferation of brain neural progenitor cells in the subventricular zone of the lateral ventricles. Immunohistochemical and stereological analyses reveal that these initial changes are followed by the gradual reappearance of myelinated cortical fibers. This is accompanied by increased proliferation of oligodendrocytic progenitors. I found that these progenitors also differentiate to mature oligodendrocytes in brain cortex. Our findings show that the blast-induced activation of the brain neural stem/progenitor cells generates predominantly new oligodendrocytes. The capacity of these new cells to myelinate damaged and regenerating neurons will be addressed in my planned future investigation.
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.
Cardiology; Cardiovascular Disease; Internal Medicine; Apoptosis and cell death; Cell Cycle; Cell growth, differentiation and development; Gene therapy; Stem Cells
I am a researcher with formal training and practice in both general and interventional cardiology. My research expertise is in coronary physiology and physiological studies in large animals with ischemic heart disease. Based on my background, my research is focused on therapeutic approaches to effect cardiac regeneration in large animals with acute and chronic ischemic heart disease. In my laboratory, I use a preclinical porcine model of hibernating myocardium with chronic left anterior descending (LAD) coronary artery occlusion and collateral-dependent myocardium or infarcted myocardium caused by coronary ischemia-reperfusion. I have addressed the problem with several different therapeutic approaches involved in gene therapy, pharmacological and stem cell therapies. We routinely perform physiological studies on these porcine models with quantitative analyses of myocardial morphometry and immune-histochemical analyses. The information we have collected in completed work demonstrates remarkable functional recovery and myocyte regeneration in the adult porcine heart. Intracoronary adenoviral gene transfer with fibroblast growth factor (FGF-5), the HMG-CoA inhibitor pravastatin and intracoronary mesenchymal stem cells (MSCs) all stimulate the proliferation of endogenous cardiac myocytes and, to some extent, generate new myocytes and vessels. Our current work is focused on understanding the regenerative capability of cardiosphere-derived cells (CDCs) originating from heart tissue in acute or chronic ischemic myocardium. The result of this work will play an important role in advancing the care of many patients with acute and chronic ischemic heart disease. In my laboratory, I mentor research fellows through their rotation. Fellows who work in my laboratory have the unique opportunity of being exposed to large animal experimentation and learning skills related to it--in physiology and coronary angiography, as well as computed tomography (CT) and magnetic resonance imaging (MRI) techniques. Under my supervision, fellows also may work on independent projects and learn about cell biology and molecular biology, with the chance to present at international meetings and to publish as an author in international journals.
Cell growth, differentiation and development; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Signal Transduction; Inherited Metabolic Disorders; RNA
Regulation of Kidney Epithelial Cell Growth, Transport and Differentiation Our laboratory is investigating the molecular mechanisms by which hormones, growth factors and extracellular matrix proteins regulate kidney tubule epithelial cell growth and functional differentiation in vitro. An established canine kidney epithelial cell line, MDCK, and isolated "mutants" are currently being utilized to examine the actions of growth regulatory on the expression of several proteins including the Na+, K+-ATPase and laminin, a glycoprotein in the extracellular matrix. The effects of novel growth regulatory factors on the expression of proteins involved in gluconeogenesis, membrane transport, renal disease and growth control in primary renal cell cultures are being examined. Primary kidney epithelial cells differentiate into nephrons in a reconstituted extracellular matrix proteins is the subject of study.
Cell growth, differentiation and development; Microbiology; Molecular Basis of Disease; Molecular and Cellular Biology; Regulation of metabolism; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
Dr. Willsky’s research focuses on the role of oxovanadium compounds in cellular metabolism. V is a trace metal believed to be required for growth. Oral administration of oxovanadium compounds alleviates the symptoms of Diabetes in animal models and humans. The techniques of genetics, microbiology, molecular biology, biochemistry, pharmacology, magnetic resonance spectroscopy, and cell physiology are used. The diabetes-altered gene expression of genes involved in lipid metabolism, oxidative stress and signal transduction is returned to normal by V treatment of rats with STZ-induced diabetes, as demonstrated using DNA microarrays. Inhibition of tyrosine protein phosphatases is believed to be a major cause of the insulin-like effects of V. Our results implicate the interaction of V with cellular oxidation-reduction reactions as being important in the anti-diabetic mechanism of V complexes. A new project in the lab studies the mode of action of medicinal plant mixtures used by the native healers of Peru.