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Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis

靶向血小板胞吞作用和胞吐作用来控制血栓形成

基本信息

批准号：
10392316
负责人：
SIDNEY Waldo WHITEHEART
金额：
--
依托单位：
VA MEDICAL CENTER - LEXINGTON, KY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392316
关键词：
Acute Address Adhesions Affect Age Aging Amino Acid Sequence Autophagocytosis Biochemical Biological Assay Blood Platelets Blood Vessels Cardiovascular Diseases Caring Carotid Artery Injuries Cause of Death Cell physiology Cellular biology Cessation of life Clot retraction Coagulation Process Communicable Diseases Complex Cytoplasmic Granules Data Disease Endocytosis Equilibrium Event Exocytosis Female Fibrinogen Gene Deletion Goals Growth Guanosine Triphosphate Phosphohydrolases Health Hemorrhage Hemostatic function Hyperactivity In Vitro Infarction Integrins Knock-out Knockout Mice Knowledge Mediating Membrane Membrane Fusion Mission Modeling Molecular Molecular Chaperones Molecular Probes Morbidity - disease rate Mouse Strains Mus Myocardial Infarction Pathology Patients Physicians Precision Medicine Initiative Process Prognosis Protein Biochemistry Proteins Publishing RNA Splicing Reaction Risk Risk Factors Role S-nitro-N-acetylpenicillamine SNAP receptor Sampling Stroke Tail Therapeutic Intervention Thrombosis Thrombus Transgenic Mice Translations Veterans Work base clinically significant experimental study familial hemophagocytic lymphohistiocytosis genome wide association study glycosylation granuphilin health management improved in vitro Assay in vivo insight male military veteran mortality platelet function protein protein interaction recruit response restenosis risk variant synaptotagmin syntaxin syntaxin 11 syntaxin A syntaxin-2 target SNARE proteins targeted treatment therapeutic target thrombotic trafficking treatment strategy vesicular SNARE proteins

项目摘要

World-wide, spurious thrombosis accounts for 1 of 4 non-communicable disease deaths. Cardiovascular disease is a leading killer of aging US veterans and is the major cause of death in older female veterans. Understanding how to modulate thrombosis will significantly aide the VA's mission to improve veterans' health. Normally platelets respond to vascular damage and secrete granule cargo that are essential for recruiting more platelets and for generating a thrombus. This releasate promotes normal sequelae but can also contribute to occlusive pathologies such as strokes and heart attacks. In platelets, VAMPs, SNAP-23, and Syntaxin-11 form a membrane-spanning complex that mediates exocytosis. Formation of this complex requires a host of SNARE-regulators, e.g., Munc18b, STXBP5/tomosyn-1, and granuphilin/SLP4; however, the mechanisms by which these proteins control the complexity of the platelet release reaction (its rate, extent, and content) is uncertain. Platelets are also capable of other cellular processes (i.e., RNA splicing, translation, glycosylation, autophagy); however, their effects on platelet function are still unknown. Our data suggest that endocytosis affects thrombus growth by modulating platelet spreading and platelet-platelet contacts. Our goal is to manipulate the membrane trafficking in platelets, both endocytosis and exocytosis, in order to modulate occlusive thrombosis with only modest effects on hemostasis. To reach this goal, we must probe the molecular mechanisms of exocytosis. Our specific focus will be on Syntaxin-11 regulators. We will also use an endocytosis defective mouse strain to define the roles of endocytosis in thrombosis and hemostasis. Two aims are proposed: 1) Define the network of protein-protein interactions that affect Syntaxin-11-mediated membrane fusion and granule cargo release; and 2) Determine the roles of platelet endocytosis in hemostasis. To complete these aims, we will employ biochemical assays to define the interactions between the SNARE regulators and in vitro and in vivo functional assays, using transgenic mice, to define the roles of the specific Syntaxin-11 regulators and of endocytosis in thrombosis and hemostasis. Our results will expand the understanding of the molecular requirements and the sequence of protein-protein interactions controlling platelet exocytosis. We will also expand the mechanistic understanding of what cellular processes platelets can perform (i.e., endocytosis) and why they are important. Our results will be significant to the field since they will provide the needed mechanistic insights to identify potential targets for therapeutic intervention and to evaluate the relevance of the increasing volume of gene/risk associations that are guiding patient treatment strategies. This will enhance the anti-thrombotic treatment options available for the care of aging veterans.

在世界范围内，假性血栓形成占非传染性疾病死亡的四分之一。心血管疾病是美国老年退伍军人的主要杀手，也是老年人死亡的主要原因。女性退伍军人了解如何调节血栓形成将大大有助于VA的使命，改善退伍军人的健康。正常情况下，血小板对血管损伤有反应，并分泌颗粒货物这是募集更多血小板和产生血栓所必需的。此次发布会促进了正常的后遗症，但也可能导致闭塞性病变，如中风和心脏病发作。在血小板、VAMP、SNAP-23和Syntaxin-11形成跨膜复合物，胞吐作用这种复合物的形成需要大量的SNARE调节剂，例如，Munc18b， STXBP 5/tomosyn-1和granuphilin/SLP 4;然而，这些蛋白质控制的机制可能是不稳定的。血小板释放反应的复杂性（其速率、程度和内容）是不确定的。血小板是也能够进行其它细胞过程（即，RNA剪接、翻译、糖基化、自噬）; 然而，它们对血小板功能的影响仍然未知。我们的数据表明内吞作用影响通过调节血小板扩散和血小板-血小板接触抑制血栓生长。我们的目标是操纵血小板的膜运输，包括内吞和胞吐，调节闭塞性血栓形成，仅对止血有适度影响。为了实现这一目标，我们必须探索胞吐作用的分子机制我们的具体重点将是Syntaxin-11 监管部门我们还将使用内吞作用缺陷的小鼠品系来确定内吞作用在血栓形成和止血。提出了两个目标：1）定义蛋白质-蛋白质网络影响突触融合蛋白-11介导的膜融合和颗粒货物释放的相互作用;以及 2)确定血小板内吞作用在止血中的作用。为了实现这些目标，我们将采用生物化学测定来确定SNARE调节剂和体外之间的相互作用，使用转基因小鼠的体内功能测定，以确定特异性Syntaxin-11的作用调节剂和内吞作用的血栓形成和止血。我们的研究结果将扩大对控制血小板的分子要求和蛋白质-蛋白质相互作用的顺序胞吐作用我们还将扩大什么样的细胞过程血小板可以机制的理解执行（即，内吞作用）以及它们为什么重要。我们的研究结果将对该领域具有重要意义，它们将提供所需的机制性见解，以确定治疗干预的潜在靶点并评估越来越多的基因/风险关联的相关性，这些关联指导患者治疗策略。这将增强可用于护理的抗血栓形成治疗选择，上了年纪的老兵