FUNCTION OF PLATELETS AND COAGULATION FACTORS

血小板和凝血因子的功能

• 批准号: 6388803
• 负责人: PHILIP W MAJERUS
• 金额: $ 59.37万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388803
• 关键词: Salmonella; bacterial genetics; cell growth regulation; chemical structure function; enzyme mechanism; gene expression; hematopoiesis; human subject; inositol phosphates; laboratory mouse; laboratory rabbit; megakaryocytes; molecular cloning; oculocerebrorenal syndrome; phosphatidylinositol 3 kinase; phosphatidylinositols; phosphorylase phosphatase; platelets; protein sequence; radioimmunoassay; site directed mutagenesis; tissue /cell culture; tumor suppressor genes; virulence

DESCRIPTION: (Adapted from the Applicant's Abstract) This grant has as its goal the elucidation of the mechanisms by which the phosphatidylinositol signalling system evokes intracellular responses to extracellular agonists. Understanding this system will provide new insights into platelet physiology and pathology and also into the proliferation and differentiation of megakaryocytes. The experiements will also address the pathogenesis of several disease states in which defects in inositol signalling are present. In particular, the applicant will study the relationship between inositol polyphosphate 4-phosphatase (4-Ptase) and phosphatidylinositol 3-kinase in platelets. He will investigate the mechanism by which 4-Ptase controls megakaryocyte proliferation in GATA-1 null megakaryocytes. In the absence of 4-Ptase, these megakaryocytes proliferate continuously and fail to produce platelets. Restoration of 4-Ptase arrests megakaryocyte growth. He will use NIH 3T3 cells to investigate whether this growth arresting property of 4-Ptase is general. He will investigate the homolog of 4-Ptase, SopB, a Salmonella gene required for virulence. In the absence of SopB, the organisms infect intestinal epithelia but fail to induce neutrophilic infiltration and diarrhea. SopB is an inositol phosphatase and enzyme activity is required for virulence. The substrate specificity and derangement of inositol metabolism in infected cells will be determined. He will study another homolog of 4-Ptase that is a tumor suppressor gene (PTEN) and is also an inositol phosphatase. The OCRL-1 5-phosphatase that when mutated is the cause of Lowe Syndrome will be examined. The applicant propose that the defect results in abnormal targeting of lysosomal enzyme in Lowe Syndrome. He plans to study this and to measure plasma lysosomal enzymes in patients with Lowe Syndrome. He will also attempt to elucidate the enzymology and regulation of production of isomers of inositol tetraphosphates and inositol pentaphosphates. He will identify, isolate, and clone cDNA for enzymes leading to InsP5 starting with inositol 1,3,4-triphosphate 5/6-kinase.

描述：（改编自申请人的摘要）这项资助的目标是阐明磷脂酰肌醇信号系统引起细胞内对细胞外激动剂的反应的机制。了解这个系统将为血小板生理学和病理学以及巨核细胞的增殖和分化提供新的见解。这些实验还将解决几种存在肌醇信号缺陷的疾病状态的发病机制。特别地，申请人将研究血小板中肌醇多磷酸4-磷酸酶(4-Ptase)和磷脂酰肌醇3-激酶之间的关系。他将研究 4-Ptase 在 GATA-1 无效巨核细胞中控制巨核细胞增殖的机制。在缺乏 4-Ptase 的情况下，这些巨核细胞会持续增殖并且无法产生血小板。 4-Ptase 的恢复可抑制巨核细胞的生长。他将使用 NIH 3T3 细胞来研究 4-Ptase 的这种生长抑制特性是否具有普遍性。他将研究 4-Ptase 的同源物 SopB，这是沙门氏菌毒力所需的基因。在缺乏 SopB 的情况下，微生物会感染肠上皮，但不能诱导中性粒细胞浸润和腹泻。 SopB 是一种肌醇磷酸酶，酶活性是毒力所必需的。将确定受感染细胞中肌醇代谢的底物特异性和紊乱。他将研究 4-Ptase 的另一种同源物，即肿瘤抑制基因 (PTEN)，也是肌醇磷酸酶。将检查 OCRL-1 5-磷酸酶，该酶突变时会导致 Lowe 综合征。申请人提出，该缺陷导致洛氏综合征中溶酶体酶的异常靶向。他计划对此进行研究并测量洛氏综合症患者的血浆溶酶体酶。他还将尝试阐明肌醇四磷酸和肌醇五磷酸异构体生产的酶学和调节。他将从肌醇 1,3,4-三磷酸 5/6-激酶开始鉴定、分离和克隆导致 InsP5 的酶的 cDNA。