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Administrative Supplements to Support Undergraduate Summer Research Experiences

支持本科生暑期研究经历的行政补充

基本信息

批准号：
10806329
负责人：
Joshua Mutambuki Muia
金额：
$ 0.9万
依托单位：
OSU CENTER FOR HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10806329
关键词：
Address Administrative Supplement Adopted Allosteric Regulation Atherosclerosis Biochemical Bioinformatics Biological Process Blood Coagulation Disorders Blood coagulation Cardiovascular Diseases Catalysis Coronary Arteriosclerosis Defect Development Diagnosis Disease Disintegrins Elements Enzymatic Biochemistry Enzymes Family Foundations Goals Grant Inflammation Inflammatory Inherited Investigation Kinetics Literature Metalloproteases Methods Modeling Molecular Conformation Outcome Peptide Hydrolases Prevention Principal Investigator Property Proteomics Reagent Regulation Reporting Research Thrombosis Thrombospondins Work biochemical tools experience human disease improved member novel protein protein interaction recruit small molecule inhibitor student mentoring summer research therapeutic target tool translational applications undergraduate student von Willebrand Factor

项目摘要

Project Summary This MIRA proposal aims to uncover the regulatory mechanisms and substrates for metalloproteases in the ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin motifs) family. These proteases are thought to be involved in many biological processes and some members are known to contribute to important human diseases. The current study focuses mainly on two members of the ADAMTS family, ADAMTS13 and ADAMTS7. Project 1 will investigate the allosteric regulation of ADAMTS13, an important regulator of blood clotting. I recently discovered that ADAMTS13 adopts a quiescent closed conformation and becomes allosterically activated by its substrate, Von Willebrand Factor (VWF). This proposal outlines a mechanistic approach to study how allosteric regulation is maintained within ADAMTS13 and disrupted by its interaction with VWF. Leveraging functional, kinetic, structural and bioinformatic analyses, this project sets to identify the key structural elements of allosteric regulation in ADAMTS13. The outcomes from this work will improve our understanding of inherited and acquired blood clotting disorders caused by defects in ADAMTS13. I also anticipate that our investigation of ADAMTS13 will serve as a model to study the regulation of other ADAMTS proteases. Project 2 focuses on ADAMTS7, which is known to contribute to coronary artery disease by promoting atherosclerosis and inflammation. However, the substrate targets of ADAMTS7 and its biochemical properties remain poorly understood. Previous attempts to address these research questions led to conflicting reports in the literature, likely due to the poor quality of reagents and tools available to study this novel protease. To circumvent these challenges, we will utilize novel methods in proteomics, enzymology, and protein-protein interactions to delineate biochemical properties and ideal substrates for ADAMTS7. Newly identified substrates will form the basis of novel biochemical tools to investigate ADAMTS7 activity and are necessary for future research goals to screen for small molecule inhibitors of ADAMTS7 that may have translational applications. Summarily, the study of ADAMTS13 and ADAMTS7 enzyme catalysis and regulation lay a foundation for our understanding of thrombotic and bleeding disorders and cardiovascular and inflammatory diseases, and these outcomes can be applied to study other ADAMTS proteases. More importantly, the MIRA offers the principal investigator an incredible opportunity to recruit and mentor students and other trainees from diverse backgrounds.

项目摘要该MIRA提案旨在揭示在细胞中金属蛋白酶的调节机制和底物， ADAMTS（一种具有血栓蛋白基序的去整合素和金属蛋白酶）家族。这些蛋白酶被认为参与许多生物过程，已知一些成员对重要的人类活动有贡献。疾病目前的研究主要集中在ADAMTS家族的两个成员，ADAMTS 13和ADAMTS 7。项目1将研究ADAMTS 13的变构调节，ADAMTS 13是血液凝固的重要调节剂。我最近发现ADAMTS 13采用静止的闭合构象，并通过其血管性血友病因子（VWF）。该提案概述了一种机制的方法来研究如何变构调节维持在ADAMTS 13内，并被其与VWF的相互作用破坏。利用功能，动力学，结构和生物信息学分析，该项目确定了变构的关键结构要素， ADAMTS 13中的监管。这项工作的结果将提高我们对遗传和获得的理解。 ADAMTS 13缺陷引起的凝血障碍。我还预计我们对ADAMTS 13的调查将作为研究其他ADAMTS蛋白酶调节的模型。项目2的重点是ADAMTS 7，已知通过促进动脉粥样硬化和炎症而导致冠状动脉疾病。但 ADAMTS 7的底物靶点及其生物化学性质仍然知之甚少。的先前尝试解决这些研究问题导致了文献中相互矛盾的报告，可能是由于质量差，可用于研究这种新型蛋白酶的试剂和工具。为了克服这些挑战，我们将利用新的蛋白质组学、酶学和蛋白质-蛋白质相互作用的方法，以描述生物化学特性， ADAMTS 7的理想底物。新发现的底物将成为新的生化工具的基础，研究ADAMTS 7活性，并为将来筛选小分子抑制剂研究目标所必需 ADAMTS 7基因可能具有翻译应用。综述了ADAMTS 13和ADAMTS 7的研究进展酶催化和调节为我们理解血栓形成和出血性疾病奠定了基础，心血管和炎症性疾病，这些结果可以应用于研究其他ADAMTS 蛋白酶更重要的是，MIRA为首席研究员提供了一个令人难以置信的机会，指导来自不同背景的学生和其他受训者。