The focus of my research is the elucidation of collagen-binding integrin structure/function mechanisms in order to understand their regulation in health and disease. Integrins are widely expressed, bidirectional signaling, transmembrane receptors essential for regulating cell growth and function. The diversity of diseases in which integrins play key roles, e.g. cancer metastasis, thrombosis, fibrosis, and diabetes, punctuates their biological importance and attractiveness as therapeutic targets. Notwithstanding their substantial potential, development of selective integrin therapeutics have been limited. Logically, rational drug design benefits from knowledge of structural mechanisms governing integrin function. The overarching question of "what is the molecular architecture of integrin-extracellular matrix (ECM) interactions and how are they disrupted in disease" guides my research. More specifically, I focus on the interactions between integrins a1b1 and a2b1 with collagens and laminins of the ECM. My philosophy is that direct observation of biological phenomena on an atomic level provides an essential basis for deciphering molecular interactions. Therefore, I subdivide my research to (1) determine integrin-ECM interactions with atomic resolution, (2) develop mechanistic models of integrin-ligand specificity and binding, (3) then test the impact of mutations and small molecules on these models. I utilize state-of-the-art biochemical, bioinformatic, structural, and computational technologies in conjunction with cell-based techniques to achieve these aims. Although initial observations are based on static structures, it is well known that motion is the basis for biological macromolecular function. While X-ray crystallography is a staple of my structural work, the innovation I bring to this endeavor is the integration of molecular dynamics simulations and NMR spectroscopy to provide time-resolved atomistic insight to integrin structure/function relationships. My ultimate goal is to use this information to guide development of more effective and safer therapeutic strategies for the treatment of fibrotic conditions.
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Key: MeSH Term KeywordAnimals Base Sequence Catalysis Chromatography, High Pressure Liquid Crystallography, X-Ray Deoxyguanosine Diabetes Mellitus, Experimental DNA DNA Adducts DNA Damage DNA Polymerase beta DNA Replication Extracellular Matrix Hypochlorous Acid Integrin Integrins Kinetics Magnetic Resonance Spectroscopy Male Mice Mice, Knockout Models, Molecular Molecular Conformation Molecular Dynamics Simulation Mutation Nitric Oxide Synthase Type III NMR spectroscopy Oligonucleotides Protein structure Rats Stereoisomerism Structural Biology Sulfolobus solfataricus Tandem Mass Spectrometry Thermodynamics X-ray crystallography