FUNCTION OF PLATELETS AND COAGULATION FACTORS

产品说明：（改编自申请人的摘要）该基金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。了解这一系统将提供新的见解，血小板的生理和病理，也到巨核细胞的增殖和分化。这些实验也将解决肌醇信号缺陷存在的几种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。他将研究在加塔-1缺失的巨核细胞中4-PTase控制巨核细胞增殖的机制。在没有4-磷酸酶的情况下，这些巨核细胞持续增殖，不能产生血小板。4-磷酸酶的恢复阻止了巨核细胞的生长。他将使用NIH 3 T3细胞来研究4-Ptase的这种生长抑制特性是否是普遍的。他将研究4-PTase的同源物，SopB，一种沙门氏菌毒力所需的基因。在不存在SopB的情况下，微生物感染肠上皮，但不能诱导嗜酸性细胞浸润和腹泻。SopB是一种肌醇磷酸酶，毒力需要酶活性。将测定受感染细胞中肌醇代谢的底物特异性和紊乱。他将研究另一种4-磷酸酶的同源物，这是一种肿瘤抑制基因（PTEN），也是一种肌醇磷酸酶。将检查OCRL-15-磷酸酶，其在突变时是Lowe综合征的原因。申请方提出该缺陷导致Lowe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Lowe综合征患者的血浆溶酶体酶。他还将试图阐明酶学和肌醇四磷酸和肌醇五磷酸异构体的生产调节。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InsP 5的酶的cDNA。

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.