UB’s New York State Center of Excellence in Bioinformatics & Life Sciences (CBLS) is home to over 250 scientists and research staff with biological, physical and computational expertise, all of whom are engaged in interdisciplinary biomedical research with collaborators from across the region, the country and the globe. CBLS faculty members are affiliated with our primary research partners, including the University at Buffalo, Roswell Park Cancer Institute, and the Hauptmann-Woodward Medical Research Institute.
PK/PD; Pharmacodynamic; Pharmacokinetic
Director, Center for Protein Therapeutics with research focusing on the utilization of pharmacokinetic and pharmacodynamic analyses and mathematical modeling to guide the discovery and development of new immunotherapies for cancer and autoimmunity. Research Interests and Projects: 1. Development of antibody conjugates for targeted, intra-cellular delivery of macromolecular toxins 2. Engineering monoclonal antibodies for improved pharmacokinetic properties 3. Investigation of sources of inter-individual variability in monoclonal antibody pharmacokinetics 4. Investigation of strategies to overcome the "binding site barrier" to antibody distribution in solid tumors 5. Development of improved mathematical models for predicting the disposition and effects of monoclonal antibody drugs 6. Development of new targeting strategies to optimize the safety and efficacy of intraperitoneal chemotherapy of ovarian cancers (CA118213) 7. Development of FcRn inhibitors for treatment of humoral autoimmune diseases (e.g., myasthenia gravis, autoimmune neutropenia) (AI60687) 8. Development of new strategies to treat immune thrombocytopenic purpura (HL67347) 9. Investigation of the role of FcRn in the absorption, distribution, and elimination of IgG antibodies 10. Development of antibody-based therapies to treat and prevent infection. Efforts are currently focused on prevention of infection by Treponema denticola (DE023080), S. aureus, and A. baumannii
Research interest is in the area of protein delivery and immunotherapy. Current research projects: 1. Development of lipidic nano particle containing therapeutic proteins and is supported by NHLBI/NIH. The overall goal of the project is to improve therapeutic efficacy of protein based therapies for bleeding and lysosomal disorders using a multidisciplinary approach involving Biophysics/Bioengineering, immunology and pharmacokinetics/Pharmacodynamics. 2. Re-activating Memory T Cells in the Microenvironment of Human Tumors and development of in situ vaccination. This project is supported by NCI/NIH (Dr. Bankert, PI, Balu-Iyer Co-PI). Our aim is to to rationally develop therapeutic intervention by understanding the molecular mechanism of TCR arrest. 3. Develop novel strategies to treat food allergies and autoimmune conditions using the tolerogenic properties of biomolecules. 4. Formulation and delivery of Monoclonal antibody based products: Understand and develop strategies to improve efficacy of antibody based therapeutics particularly given via sc route of administration
Apoptosis and cell death; Bioinformatics; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Regulation of metabolism
My laboratory studies the cell-autonomous and non-cell-autonomous mechanisms of axon degeneration, a process akin to programmed cell death. In other words, we are attempting to elucidate what causes axon breakdown from within neurons and which external (glial) events trigger axon loss. Degeneration of axons is a hallmark in many neurodegenerative conditions, including those associated with abnormal glia. We have great hope that understanding why and how axons degenerate may lead to more efficient neuroprotective therapies tailored specifically to support axons and their surrounding glia. Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system. As such, they are critical for neuronal wiring and transport of neuronal maintenance signals. Because of their incredible length and energetic demand (human motor neurons can be one meter long), however, axons are very vulnerable and at continuous risk of damage. Axons do not exist in isolation but are inextricably and intimately associated with their enwrapping glia (Schwann cells and oligodendrocytes) to form a unique axon-glia unit. The most relevant neurological symptoms in a number of debilitating neurodegenerative conditions are due to compromised axon integrity. Thus, neuroprotective therapies promoting axon stability have great potential for more effective treatment. Recent studies indicate that axonal degeneration, at least in experimental settings, is an active and highly regulated process akin to programmed cell death (‘axonal auto-destruction’). Moreover, it is increasingly realized that axonal maintenance relies not only on neuron-derived provisions but also on trophic support from their enwrapping glia. The mechanism for this non-cell-autonomous support function remains unknown, but emerging evidence indicates that it is distinct from the glial role in insulating axons with myelin. We are pursuing the intriguing question of whether abolished support by aberrant delivery of metabolites and other trophic factors from glia into axons is mechanistically linked to the induction of axonal auto-destruction. This concept is supported by our recent finding that metabolic dysregulation exclusively in Schwann cells is sufficient to trigger axon breakdown.
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Our research group is interested in how regulatory proteins are targeted to the correct DNA binding sites at the correct time. Transcription factors are directed to their genomic targets by DNA sequence, local chromatin structure, and protein-protein interactions. These modulators of transcription factor binding are not independent but function both cooperatively and competitively to regulate where transcription factors bind. Understanding how these modulators affect transcription factor binding in vivo remains a major unsolved biological problem. We use the model organism Saccharomyces cerevisiae to address the disconnect between the presence of the correct DNA binding sequence and true regulatory protein binding, integrating both experimental and computational approaches to: i) investigate transcription factor binding in response to environmental stress, ii) identify and characterize the mechanisms directing transcription factor target selection, and iii) and develop bioinformatics tools to analyze and interpret ChIP-seq experiments and chromatin structural patterns.
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.
Robin DiFrancesco, MT ASCP, MBA has over 30 years of experience in pharmacology research (20+ in HIV research) and has a variety of knowledge, practical and theoretical, to offer our global students. She is appointed at the UB School of Pharmacy and Pharmaceutical Sciences as a research assistant professor and as a voluntary adjunct faculty member for the UB Department of Biotechnology and Clinical Sciences within the Jacobs School of Medicine and Biomedical Sciences. She holds an ACSP certification as a medical technologist and a NYS license as a clinical laboratory technologist. Her experience in clinical pharmacology research and quality assurance, as it applies to the clinical pharmacology laboratory and laboratory sciences, is extensive. She has served almost 16 years in this capacity within the NIH/NIAID/DAIDS networks as well as a laboratory technologist on the ACTG/IMPAACT Laboratory Technoligists committee. She is also appointed as the scientific manager of the Drug Development Core, part of the Clinical and Translational Science Institute at the University at Buffalo. In addition, she has served as both vice-chair and chair on two specialty sections for The Society for Quality Assurance. Robin has co-authored and published over 60 articles.
Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating disease.
Dr. Furlani serves as Director of the University at Buffalo‘s Center for Computational Research (CCR), a leading academic supercomputing center. As Director of CCR, Dr. Thomas Furlani, whose Ph.D. is in Computational Chemistry, manages the day-to-day operations of the center as well as oversees its research activities. A National Science Foundation Pre-doctoral Fellow, Dr. Furlani has more than 25 years experience in research computing and visualization, including high-performance computing, computational chemistry, and cloud computing. In addition to supporting research, Education and Outreach has been an important component of CCR‘s mission since its inception, with on-going K-12, undergraduate and graduate level programs. In terms of K-12 outreach, CCR each year runs the Eric Pitman Annual Summer Workshop in Computational Science.
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).
Dr. Jeffrey Lombardo is Associate Director for UB’s patient safety organization Empire State Patient Safety Assurance Network. In this role he facilitates organization participation, logistics and implementation with participating sites as well as reviewing data and presenting reports on findings. Working with Medical Oncologists he is tracking patient outcomes and advising physicians on best practices for cancer patients making full use of his specialty pharmacy certification in oncology. Dr. Lombardo is also a member of the SUNY Global Health Institute where he will be bringing his patient safety and oncology expertise to partner schools like the University of the West Indies for various collaborations.In Jamaica he will be partnering with UWI on studies on medical marijuana and pursuing new initiatives for the University at Buffalo’s medication management research network. (MMRN) Additionally Dr. Lombardo is a member of UB‘s Center for Integrated Global Biomedical Sciences. Dr. Lombardo received his Doctorate in Pharmacy from the University at Buffalo where he currently holds a Research Assistant Professor Title. He has completed research and co-authored several articles on topics involving chemotherapy in the field of solid tumors. Dr. Lombardo has worked in various cancer pharmacies throughout Western New York as well a national oncology specialty pharmacy. These roles provided Dr. Lombardo with expertise in contracting with managed care plans and companies in the pharmaceutical industry. In addition to these accomplishments Dr. Lombardo has exhibited and presented his work at the American Society of Clinical Oncology, American Society of Health System Pharmacists and Value Based Cancer Care Symposiums.”
Research interests areas: 1. Pharmacogenomics of antiretrovirals in patients with HIV-associated neurocognitive disorders 2. Mechanisms of drug-drug interactions in patients with HIV infection 3. Incorporating pharmacokinetics, pharmacodynamics and pharmacogenomics in studying the effects of antiretrovirals on the central nervous system
Gene D. Morse, Pharm.D., FCCP, BCPS, is a tenured, SUNY Distinguished Professor in the School of Pharmacy and Pharmaceutical Sciences and Director of the UB Center for Integrated Global Biomedical Sciences. He is also the Co-Director of the SUNY Global Health Institute. Dr. Morse has been actively involved in drug development research since the introduction of antiretrovirals for HIV in 1986, with more recent emphasis on HCV infection and drug development. He has National Institute of Allergy and Infectious Diseases support for the UB AIDS Clinical Trials Group, Pharmacology Specialty Laboratory and a contract for the HIV Clinical Pharmacology Quality Assurance Program. These programs integrate with the NIH Fogarty International Center AIDS International Training and Research Program, which Dr. Morse directs with the University of Zimbabwe and is home to the Center of Excellence in Clinical Pharmacology. Dr. Morse also directs the UB HIV Clinical Pharmacology Laboratory, which has gained an international reputation for its work in bioanalysis, pharmacokinetics, and pharmacogenomics. In addition, Dr. Morse is director of the Empire State Patient Safety Assurance Network, a federally certified patient safety organization and a network for health information technology innovation. Dr. Morse is the director of the UB Translational Pharmacology Research Core. He is also associate director for the Clinical Trials Methods and Technologies Pillar for the Clinical and Translational Sciences Institute at the University of Rochester Medical Center. Dr. Morse is co-founder of the Buffalo Jamaica Innovation Enterprise, a partnership between UB the University of the West Indies and the Jamaica Ministry of Health. This project has established the Jamaica Center for Infectious Diseases Research. Dr. Morse has more than 25 years of NIH, industry and philanthropic research support with extensive experience in grant applications and mentoring. Dr. Morse received the 2012 Volwiler Research Achievement Award from the American Association of Colleges of Pharmacy.
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.
Ion channel kinetics and structure; Molecular and Cellular Biology; Neurobiology; Neuropharmacology
Our research program focuses on brain development, studying the development of the oligodendroglial and astroglial cell lineages in the central nervous system in normal, mutant and transgenic mice. The primary focus in the laboratory is on ion channels that regulate specification, migration and differentiation of these glial cells. The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently discovered that voltage-gated Ca++ channels are necessary for normal myelination acting at multiple steps during oligodendrocyte progenitor cells (OPCs) development, however nothing is known about its role in demyelination or remyelination events. Our research aims to determine if voltage-gated Ca++ channels plays a functional role in myelin repair. Using transgenic mice and new imaging techniques we are testing the hypothesis that voltage-gated Ca++ entry promotes OPC survival and proliferation in the remyelinating adult brain. Therefore, this work is relevant to developing means to induce remyelination in myelin degenerative diseases and for myelin repair in damaged nervous tissue. Astrocytes are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood brain barrier, provision of nutrients to the nervous tissue and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries. Our lab has made the novel finding of voltage-gated Ca++ channels function in astrocyte Ca++ homeostasis, and this has implications for plasticity in astrocyte development and for Ca++ regulation in general. We are testing the hypothesis that voltage-gated Ca++ entry plays a key role in astrocyte function and glial-neuronal interactions. We have generated a conditional knockout mice for voltage-gated Ca++ channels in astrocytes, these conditional knockout mice will allow the functional analysis of voltage-gated Ca++ channels in astroglia of the postnatal and adult brain. Analyzing such mice using a combination of behavioral, electrophysiological, imaging, and immunohistochemical techniques will provide new insights in our understanding of astroglial contribution to brain function. These projects have been supported for many years by grants from the NIH and the National Multiple Sclerosis Society.
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.
Research focus areas: Proteomics and Pharmaceutical Analysis. Major research programs in the proteomic field involve i) high-resolution and large-scale expression profiling of pathological proteomes (e.g. for cardiovascular diseases, colon cancer and infectious diseases) for the discovery of disease/therapeutic biomarkers by gel-free LC/MS methods; ii) Sensitive identification, localization and quantification of post-translational modifications in complex proteomes, with the emphases on arginine methylation and phosphorylation. Novel anti-PTM-peptides capture procedure and alternating collision induced dissociation (CID)/electron transferring dissociation (ETD) are employed to obtain abundant PTM information; iii) targeted quantification of regulatory, marker proteins for clinical study. Dr. Qu‘s lab possesses many state-of-the-art LC/MS instruments, including a high resolution/accuracy LTQ/Orbitrap XL with ETD, a highly sensitive TSQ Quantum Ultra EMR triple-quadrupole instrument, two ultra-high pressure nano-LC systems, and several HPLC instruments for pre-fraction and ion chromatography. A number of key analytical advances have been developed by his lab that greatly enhanced the proteomic coverage, sensitivity and throughput for proteomic research. As for the Pharmaceutical Analysis of small-molecule drug/markers, Dr. Qu‘s lab is focusing on the ultra-sensitive quantifications of drug, metabolites and endogenous markers (e.g. corticosteroids, di-hydroxyl-vitamin D metabolites, androgens, etc.) using a novel combination of selective enrichment and micro- or nano- LC/MS.
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.
Barry Smith is a prominent contributor to both theoretical and applied research in ontology, especially in the biomedical domain. He is the author of some 500 publications on ontology and related topics, and editor of The Monist: An International Quarterly Journal of General Philosophical Inquiry. His research has been funded by the National Institutes of Health, the US, Swiss and Austrian National Science Foundations, the US Department of Defense, the Volkswagen Foundation, and the European Union. In 2002 he received the 2 million Euro Wolfgang Paul Award of the Alexander von Humboldt Foundation and in 2010 he was awarded the first Paolo Bozzi Prize in Ontology by the University of Turin. Smith is SUNY Distinguished Professor in the Department of Philosophy and Director of the National Center for Ontological Research in the University at Buffalo (UB). He is also Adjunct Professor in the UB Departments of Biomedical Informatics, Computer Science and Neurology. Smith’s pioneering work on the science of ontology led to the formation of the OBO (Open Biomedical Ontologies) Foundry, a suite of resources designed to support information-driven research in biology and biomedicine. He is ontology lead for the NIAID ImmPort project, one of the principal scientists of the National Center for Biomedical Ontology, a Scientific Advisor to the Gene Ontology Consortium, and a PI on the Protein Ontology and Infectious Disease Ontology projects. He also provides ontology support to the United Nations Environment Program, the US Army Intelligence and Information Warfare Directorate (I2WD) and other defense agencies. Since 2009 Smith has also served as ontology consultant to Hernando de Soto of the Institute of Liberty and Democracy (ILD) supporting the work of the ILD on creating modern legal frameworks that help the poor of the developing and ex-communist world access property and business rights.
Our research program involves the application of drug carriers for the treatment of infectious diseases and cancer. Recent past efforts have been directed toward improving the therapy of brain tumors (as well as others) by targeting tumor blood vessels. Currently we are investigating strategies in increase the perfusion and drug permeability of pancreatic cancers by compromising the ability of cells within the tumor stroma, or extracellular matrix, to maintain the very low tumor blood supply and impermeability to drugs and nanoparticles We employ a variety of experimental approaches, including high-resolution magnetic resonance imaging, liquid chromatography/mass spectrometry, confocal fluorescence microscopy and image analysis, pharmacokinetic/dynamic analysis, and molecular techniques such as quantitative RT-PCR and proteomics. With these techniques, we examine the effects of treatment upon tumor vascular permeability and drug deposition, the localization of the carrier-delivered drug within the tumor, and the molecular mechanisms involved when tumor blood vessels or tumor stroma are attacked during therapy. Additional interests of the lab that are being pursued actively include understanding the mechanisms of anti-cancer drug action and how they may be modified by changing exposure profile (time vs. concentration). Both genomic and proteomic analysis approaches are utilized in this work, but an approach of increasing importance to our research is the implementation of comprehensive proteomic investigations in order to understand in detail how tumors respond to standard-of-care drugs and new molecularly-targeted drugs.
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.
Research works focuses in the area of Clinical Pharmacokinetic and Pharmacodynamic Research of Immunosuppressive Regimens in Renal Transplantation. This clinical research program has been an ongoing collaborative program with the Division of Nephrology at Erie County Medical Center for over 15 years focusing on the pharmacokinetics, pharmacodynamics and pharmacogenomics of immunosuppressive agents during renal transplantation:
Current and upcoming clinical research endeavors focus upon pharmacokinetics of immunosuppressive drugs in relationship to pharmacodynamics of immunologic markers and targeted pharmacogenomic endpoints in relation to race and gender of the renal transplant recipient. Research projects may provide the student with exposure to a variety of biomedical technologies including LCMSMS, flow cytometry and Q-PCR. These projects provide Pharm.D. students with an opportunity to explore clinical and translational research projects though a clinical research team (i.e. Pharm.D.s, physicians, nurse clinicians, immunologists, geneticists, biostatisticians, etc.) by participation in clinical pharmacology sub-studies in renal transplant patients with the endpoint to provide safe and efficacious immuosuppression (e.g. cyclosporine, prednisone, mycophenolic acid) among different patient groups.
In addition, this funded clinical research program has focused on the pharmacokinetics and dynamics of glucocorticoids with specific emphasis on the impact of the factors of gender, race, acute rejection, time post-transplant, immunologic response and chronic adverse effects in the renal transplant population. This research program has also evaluated the pharmacodynamics of anti-lymphocyte induction agents as well as glucocorticoid pharmacokinetics during various "steroid withdrawal" protocols during a multi-center clinical trial.
I am Clinical and Translational Pharm.D. Scientist and PI of R01AI111990 which seeks to investigate the Pharmacokinetics and Pharmacodynamics of Polymyxin Combinations. This R01 is interdisciplinary and blends diverse areas including microbiology and antimicrobial pharmacology with next generation sequencing and a number of infection models with an outstanding team of Pharm.D., M.D., and Ph.D. Co-Investigators. I am an internationally leading expert on antimicrobial pharmacology. In my early work in at Wayne State University, I completed new studies to optimize vancomycin dosing to combat heterogeneous resistance in Staphylococcus aureus by using PK/PD approaches to evaluate novel dosage regimens and antibiotic combinations. With the recent spread of multidrug-resistant Gram-negative bacteria, at the University at Buffalo, I developed an independent, federally funded research program, and expanded my research to refine exposure response approaches in a number of agents including colistin, polymyxin B, beta-lactams, and new combinations involving beta-lactam inhibitors against these very problematic pathogens. From 2008 to 2012, I have been a Co-investigator and PI of a subcontract at the University at Buffalo for R01A1079330 (PI Nation), a $2.3 million award from NIH. I am currently Principal Investigator of R01AI111990 a $4.4M grant which seeks to investigate the Pharmacokinetics and Pharmacodynamics of Polymyxin Combinations.
Developmental Neurology; Neurology
My laboratory has a longstanding interest in myelin and its diseases. Myelin surrounds large axons and permits rapid conduction of signals. It is formed by oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. During development, these cells migrate with the axons that they will myelinate, and depend on those same axons for appropriate signals to survive and differentiate. Myelin-forming glia coordinately express a unique set of genes encoding myelin structural proteins, and enzymes that synthesize myelin lipids-this coordination is in large part transcriptionally-mediated. Given the unique three dimensional transformation of the cell required for myelination, many of the involved proteins include adhesion among their functions. Therefore, our projects include studies of transcriptional regulation, axonal signals to myelinating glia, the role of adhesion in myelination and the characterization of animal models of human demyelinating diseases.