权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Proteomic studies of normal and abnormal platelet function

正常和异常血小板功能的蛋白质组学研究

基本信息

批准号：
7295726
负责人：
LAWRENCE F BRASS
金额：
$ 19.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-22 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295726
关键词：
Abnormal Platelet Address Affect American Biological Biology Blood Blood Platelets Cancer Biology Cardiology Cell Adhesion Molecules Cell Surface Receptors Cells Clinical Coagulation Process Collaborations Complement Complex Mixtures Core Facility Coupled Data Data Collection Defect Disease Disease susceptibility Doctor of Philosophy Electrophoresis Endopeptidases Event Functional disorder Funding Gene Expression Genetic Genetically Engineered Mouse Genomics Goals Growth Hematology Hemophilia A Hemorrhage Hemostatic function Human In Vitro Inbred Mouse Individual Individual Differences Inherited Institutes Laboratories Liquid Chromatography Mass Spectrum Analysis Measures Medical Medicine Megakaryocytes Membrane Proteins Methodology Methods Molecular Molecular Diagnosis Mus Mutation Numbers Pathologic Patients Pediatrics Pennsylvania Peptide Hydrolases Pharmaceutical Preparations Pharmacology Plasma Platelet Activation Platelet Count measurement Platelet aggregation Predisposition Principal Investigator Process Proteins Proteome Proteomics Protocols documentation RNA Red Cross Research Design Research Personnel Rest Role Sampling Set protein Signal Transduction Surface Techniques Technology Testing Therapeutic Thrombosis Thrombus Time Transfusion Uncertainty University Hospitals Work base brass cell type cohort experience hospital laboratories in vivo insight interest member novel oncology professor programs response single molecule stable isotope success two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Many useful insights into normal and pathologic platelet function have come through studies that focused on single molecules. There are, however, many unanswered questions that do not lend themselves to a "one molecule at a time" approach. These questions would benefit from the application of technologies that can identify complex mixtures of proteins in a quantitative manner using amounts of blood that can reasonably be obtained from single individuals or small numbers of inbred mice. Some of those questions will be addressed in the studies that comprise this proposal. The goal of the first specific aim is to define the components of the platelet sheddome - the set of proteins that are proteolytically shed from the platelet surface when platelets are activated. Protein shedding from platelets releases bioactive molecules into the surrounding plasma. Shedding can also alter the function of essential cell surface receptors, thereby modulating thrombus growth and the interaction of platelets with other types of cells. The goal of the second aim is to understand how the loss of critical signaling and adhesion molecules, either by mutation or by the long term administration of therapeutic antagonists, can have unanticipated effects on the expression of other proteins. Such compensatory changes are of interest because of the insights that they can provide into the normal events of platelet activation, and because of their potential relevance to differences among individuals that may affect susceptibility to disease and responses to anti-platelet agents. The third specific aim will address the molecular basis for the decrease in platelet function and survival that occurs when human platelets are stored prior to transfusion. We will test the hypothesis that these changes are due in part to the shedding of critical membrane proteins. The fourth specific aim will test the hypothesis that an unbiased screen of the platelet proteome can help to establish a molecular diagnosis when other methods have failed to do so. Studies will be performed on platelets from two cohorts of patients with clinical evidence for platelet dysfunction, but no established molecular diagnosis. Each of the proposed studies rests on the combined experience in clinical hematology, transfusion medicine, platelet activation and proteomic technologies represented by the PI, co-PI and their collaborators. The studies are designed using methods that we have recently applied to the identification of platelet membrane proteins. This includes novel methods that permit quantitation of individual molecules so that changes in levels of expression can be measured.

描述（由申请人提供）：对正常和病理性血小板功能的许多有用的见解来自于专注于单分子的研究。然而，还有许多未回答的问题不适合“一次一个分子”的方法。这些问题将受益于技术的应用，这些技术可以使用可以从单个个体或少量近交系小鼠中合理获得的血液量以定量方式识别复杂的蛋白质混合物。其中一些问题将在构成本提案的研究报告中讨论。第一个具体目标的目标是定义血小板脱落层的组成部分-当血小板活化时从血小板表面蛋白水解脱落的一组蛋白质。从血小板脱落的蛋白质将生物活性分子释放到周围的血浆中。脱落还可以改变必需细胞表面受体的功能，从而调节血栓生长和血小板与其他类型细胞的相互作用。第二个目标的目的是了解关键信号传导和粘附分子的丢失，无论是通过突变还是通过治疗性拮抗剂的长期施用，如何对其他蛋白质的表达产生意想不到的影响。这种代偿性变化是令人感兴趣的，因为它们可以提供对血小板活化的正常事件的见解，并且因为它们与可能影响疾病易感性和抗血小板药物反应的个体差异的潜在相关性。第三个具体目标将解决在输血前储存人血小板时发生的血小板功能和存活率降低的分子基础。我们将测试的假设，这些变化是由于部分脱落的关键膜蛋白。第四个具体目标将测试的假设，即一个公正的筛选血小板蛋白质组可以帮助建立一个分子诊断时，其他方法都未能做到这一点。将对来自两个具有血小板功能障碍临床证据但未确定分子诊断的患者队列的血小板进行研究。每项拟定研究均基于PI、共同PI及其合作者代表的临床血液学、输血医学、血小板活化和蛋白质组学技术的综合经验。这些研究是使用我们最近应用于血小板膜蛋白鉴定的方法设计的。这包括允许定量单个分子的新方法，以便可以测量表达水平的变化。