Cell Adhesion Mechanisms in Vascular Disease and Thrombosis

血管疾病和血栓形成中的细胞粘附机制

• 批准号: 7539177
• 负责人: Mark HOWARD Ginsberg
• 金额: $ 212.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539177
• 关键词: Cell; Adhesion; Mechanisms; Vascular; Disease

DESCRIPTION (provided by applicant): Support is requested to continue a program designed to advance understanding of molecular mechanisms of vascular disease and to promote development of new diagnostic, therapeutic, and preventive strategies through the collaborative efforts of a group of experienced scientists focused on the unifying theme of cell adhesion. These studies will span analysis of biochemistry, fine structure at atomic level detail, ex-vivo studies to analyze the effects of blood flow on adhesion and signaling, hematopoiesis, and analysis of genetically modified mice. Dr. Ginsberg will study talin, a cytoskeletal protein, and its interactions with beta3 integrins and the succeeding consequences for activation of integrin alpha IIb beta 3 (GPIIb-IIIa) and resulting platelet aggregation and thrombosis. Specific studies will address the regulation of talin binding to the integrin, the mechanism by which talin induces activation of integrin alpha IIb beta 3, and the in vivo and ex vivo consequences of perturbing that interaction. Dr. Kaushansky will study the developmental biology of adhesive signaling in the platelet lineage. A major focus will be the intersection between adhesive and thrombopoietin signaling in hematopoietic stem cells, megakaryocytes and platelets and the consequences of this intersection for platelet thrombus formation. Dr.Shattil will continue to develop and utilize strategies to manipulate the expression and study the function of integrin alpha IIb beta 3 and other genes in mouse megakaryocytes and platelets, both ex vivo and in vivo. A central focus will be the mechanisms and consequences of the association of c-Src and Protein Kinase C with alpha IIb beta 3 in platelets and megakaryocytes. Dr. Ruggeri will build on recent advances in the structure of von Willebrand Factor (vWF) and platelet GPIb. Specific foci will be on the biomechanical properties of the bonds between GPIb and vWF in flowing blood and intracellular signaling pathways that connect this interaction to platelet aggregation. A mouse genetics core, directed by Dr. Marth, will provide expertise, genomic constructs, genotyping, well characterized murine embryonic stem cells, and blastocyst injections for the purpose of genetic manipulation of mice and ES cells. This core will be used to generate integrin beta3 knock ins that selectively perturb interactions with Src kinases or with talin and talin knock ins that disrupt integrin activation, phosphorylation, or phosphoinositide binding. An administrative core will continue to provide administrative support.

描述（由申请人提供）： 要求支持继续一项计划，旨在通过一组专注于细胞粘附的统一主题的经验丰富的科学家的合作努力来促进血管疾病分子机制的理解，并促进新的诊断，治疗和预防策略的发展。 这些研究将涵盖生物​​化学，原子水平细节的精细结构，前体研究，以分析血流对粘附和信号传导的影响，造血和遗传修饰的小鼠的分析。 Ginsberg博士将研究塔林（Talin），一种细胞骨架蛋白及其与β3整合蛋白的相互作用以及对整联蛋白alpha iib beta 3（GPIIB-IIIA）激活的后果以及导致的血小板聚集和血栓形成。具体的研究将解决塔林与整联蛋白的结合的调节，塔林诱导整联蛋白alpha iib beta 3的激活的机制，以及使这种相互作用扰动的体内和离体后果。 Kaushansky博士将研究血小板谱系中粘附信号传导的发育生物学。 主要的重点是造血干细胞，巨核细胞和血小板中粘合剂和血小板素信号传导之间的相交，以及该交集对血小板血栓形成的后果。 Shattil博士将继续制定和利用策略来操纵整合蛋白alpha iib beta 3和其他基因在小鼠巨核细胞和血小板中的表达和功能，均在体内和体内。中心重点是C-SRC和蛋白激酶C与血小板和巨核细胞中αIIIBBeta 3的缔合的机理和后果。 Ruggeri博士将建立在von Willebrand因素（VWF）和Platelet GPIB结构的最新进展基础上。在流动的血液和细胞内信号传导途径中，将这种相互作用连接到血小板聚集的流动性血液和细胞内信号传导途径中，特定的焦点将是GPIB和VWF之间键的生物力学特性。 由Marth博士执导的小鼠遗传学核心将提供专业知识，基因组构建体，基因分型，表征良好的鼠类胚胎干细胞和胚泡注射，以进行小鼠和ES细胞的基因操纵。该核心将用于生成整合素beta3敲击INS，以选择性地与SRC激酶或Talin和Talin敲击INS进行有选择性的扰动相互作用，从而破坏整联蛋白激活，磷酸化或磷酸固醇结合。 行政核心将继续提供行政支持。