Role of PIKFyve in platelet-mediated inflammation and thrombosis

PIKFyve 在血小板介导的炎症和血栓形成中的作用

基本信息

批准号：
8968009
负责人：
Sang H. Min
金额：
$ 13.39万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968009
关键词：
1-Phosphatidylinositol 4-Kinase Ablation Actins Acute myocardial infarction Adhesions Advisory Committees Antibodies Atherosclerosis Award Biochemical Biochemical Pathway Biological Assay Biology Blood Platelets Blood Vessels Carotid Artery Injuries Cathepsins Cell Communication Cells Cellular biology Cessation of life Communication Cytoplasmic Granules Data Defect Development Diagnosis Discipline Disease Doctor of Philosophy Endothelial Cells Endothelium Environment Enzyme-Linked Immunosorbent Assay Enzymes Equipment Fellowship Figs - dietary Fostering Genes Goals Hair Hematology Hemostatic Agents Homeostasis Image Immune Immune system Immunoblotting In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Internal Medicine K-Series Research Career Programs Knowledge Learning Life Lipids Liver Lysosomes Mammals Mediating Mediator of activation protein Medicine Megakaryocytes Mentorship Microarray Analysis Microscopy Molecular Biology Morbidity - disease rate Mus Pathogenesis Pathology Pathway interactions Pennsylvania Phosphotransferases Physicians Plasma Play Process Protein Secretion Publishing Research Research Personnel Research Training Residencies Resistance Role Scientist Secretory Vesicles Signal Transduction Staining method Stains Testing Thrombosis Thrombus Time Tissues Training Training Programs Transcriptional Activation Universities Vascular System Vesicle Weight Gain Work base brass career cellular imaging college in vivo insight instructor lysosomal proteins macrophage member mortality novel oncology protein expression public health relevance response skills trafficking transcription factor von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): This K08 Career Development Award details a five-year training program to foster the career goal of Dr. Sang H. Min to become an independent investigator in megakaryocyte and platelet biology. Dr. Min is currently an Instructor in Medicine at the University of Pennsylvania. She completed a residency in Internal Medicine at Albert Einstein College of Medicine and a fellowship in Hematology-Oncology at the University of Pennsylvania. Recently, she also defended a Ph.D. in Cell and Molecular Biology at the University of Pennsylvania. During the course of the award period, Dr. Min will learn new scientific knowledge, acquire new skills, and carry out the proposed research and training under the mentorship of Drs. Charles S. Abrams and Mortimer Poncz. To enhance her scientific and professional development, an advisory committee of world- renowned physician-scientists in different disciplines has been assembled. The members of her advisory committee are Drs. Garret Fitzgerald, Lawrence F. Brass, and Mark L Kahn. The rich environment provided by the University of Pennsylvania has all the necessary facilities, equipment, expertise, and training for Dr. Min to complete her project successfully. The proposed research will focus on the role of platelet lysosomes in inflammation and thrombosis. Platelet secretory-products are believed to be crucial mediators in crosstalk between platelets and both endothelial and immune cells. However, the mechanisms by which this platelet- driven process leads to the development of inflammation and thrombosis are poorly understood. Dr. Min's long-term goal is to understand how platelets mediate cell interactions that promote inflammation and thrombosis, and identify potential targets for diagnosis and therapy. In a recently published work, Dr. Min demonstrated that platelet-specific inactivation of PIKfyve, a lipid kinase that modulates intracellular trafficing in mammals, disrupted the platelet lysosomal homeostasis and induced inflammatory and thrombotic responses in mice. This K08 proposal builds on this published work and proposes to understand normal role of PIKfyve in platelets, and how this lipid kinase contributes to a crosstalk between platelets and innate immune cells. The central hypothesis is that PIKfyve-null platelets release their lysosomes, which in turn induces tissue macrophages to drive inflammatory and thrombotic responses. The specific aims are: 1) Determine how PIKfyve regulates the platelet lysosomal homeostasis; 2) Define how PIKfyve-null platelets crosstalk with macrophages to promote inflammation; and 3) Determine how PIKfyve in platelets contributes to arterial thrombosis. Together, the results of this proposal are expected to provide mechanistic insights into how PIKfyve regulates platelet lysosomes as well as platelet-mediated communication with immune and vascular cells. These studies may identify potential targets for the diagnosis and therapy of platelet-mediated hemostatic and non-hemostatic diseases.

描述（由申请人提供）：该 K08 职业发展奖详细介绍了一项为期五年的培训计划，以促进 Sang H. Min 博士成为巨核细胞和血小板生物学的独立研究者的职业目标。Min 博士目前是巨核细胞和血小板生物学的讲师。她在宾夕法尼亚大学完成了内科住院医师培训，并在宾夕法尼亚大学获得了血液肿瘤学博士学位。在宾夕法尼亚大学分子生物学和分子生物学领域，Min 博士将在 Charles S. Abrams 和 Mortimer 博士的指导下学习新的科学知识，获得新的技能，并进行拟议的研究和培训。为了促进她的科学和专业发展，她组建了一个由不同学科的世界知名医师科学家组成的咨询委员会，其成员包括 Garret Fitzgerald 博士、Lawrence F. Brass 博士和 Mark L 博士。宾夕法尼亚大学提供的丰富环境拥有所有必要的设施、设备、专业知识和培训。敏博士成功完成了她的项目，研究重点是血小板溶酶体在炎症和血栓形成中的作用。血小板分泌产物被认为是血小板与内皮细胞和免疫细胞之间相互作用的关键介质。人们对这种血小板驱动的过程导致炎症和血栓形成的机制知之甚少，Min 博士的长期目标是了解血小板如何介导促进炎症和血栓形成的细胞相互作用，并确定潜在的靶标。在最近发表的一项研究中，Min 博士证明了 PIKfyve（一种调节哺乳动物细胞内运输的脂质激酶）的血小板特异性失活会破坏血小板溶酶体稳态并诱导小鼠的炎症和血栓反应。基于这项已发表的工作，并建议了解 PIKfyve 在血小板中的正常作用，以及这种脂质激酶如何促进血小板和先天免疫之间的串扰核心假设是 PIKfyve 无效的血小板释放其溶酶体，进而诱导组织巨噬细胞驱动炎症和血栓反应。具体目标是：1) 确定 PIKfyve 如何调节血小板溶酶体稳态；无效血小板与巨噬细胞相互作用促进炎症；以及 3) 确定 PIKfyve 的作用机制总之，该提案的结果有望为 PIKfyve 如何调节血小板溶酶体以及血小板介导的与免疫和血管细胞的通讯提供机制见解。这些研究可能会确定诊断和治疗的潜在靶标。血小板介导的止血和非止血疾病。