ABNORMALITIES OF PLATELET CALCIUM IN DISEASE

疾病中血小板钙异常

• 批准号: 3471335
• 负责人: J Anthony Ware
• 金额: $ 11.32万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471335
• 关键词: angina pectoris; binding proteins; biological signal transduction; blood chemistry; calcium binding protein; calcium channel blockers; calcium flux; cardiovascular disorder chemotherapy; cardiovascular pharmacology; cyclic AMP; disease /disorder proneness /risk; drug interactions; drug receptors; fibrinogen; fluorescence spectrometry; fluorescent dye /probe; human subject; human therapy evaluation; luminescence; marine animal oil; molecular pathology; myocardial infarction; nutrition related tag; omega 3 fatty acid; phosphorylation; platelet activation; platelet aggregation; platelet disorder; platelets; protein kinase C; radiotracer; second messengers; stimulus /response; thrombosis; thromboxanes; uremias

Many systemic diseases are associated with abnormalities in platelet aggregation and storage granule secretion, but the biochemical basis for this disordered function is unknown. The major aims of these studies are to evaluate abnormalities in stimulus-response coupling of platelets taken from patients with thrombotic cardiovascular disease, to determine the effects of therapeutic interventions given to these patients on platelet function, and to assess the importance of changes in intracellular regulators to activation of normal platelets under conditions that simulate in vivo activation. Based on our previous in vitro studies demonstrating the close link between intracellular Ca++ and platelet functional changes, my current working hypotheses are that 1) a rise in cytoplasmic ionized (Ca++) in response to one agonist "primes" the platelets for synergistic functional response to additional agonists and 2) that abnormalities in platelet Ca++ homeostasis may underlie functional alterations in thrombotic cardiovascular disease. Since aequorin and the fluorescent probes indo-1, quin2, and fura-2 appear to measure different aspects of Ca++ homeostasis, both will be used to record (Ca++) in platelets stimulated or inhibited by various agents. In normal platelets, the individual and net effects of subthreshold concentrations of several agonists will be compared to assess the role of Ca++ in synergy. Ca++ transients as seen with both indicators will be compared to other markers of platelet activation, including fibrinogen binding, and phosphorylation of platelet proteins, to identify physiologic correlates of increased (Ca++). Blood will also be obtained from patients with ischemic heart disease to determine if alterations in either resting or stimulated Ca++ or the relationship between Ca++ and other second messengers, are characteristic of these disorders. The Ca++ abnormalities will be compared to those found in platelets from patients with uremia, which is associated with a prolonged bleeding time for reasons that are unclear. Finally, the effect of certain therapeutic interventions on patients with ischemic heart disease will be tested, including fish oil and Ca++ antagonists, to better understand their mechanism of action. These studies should provide a greater understanding of platelet stimulus-response coupling in vivo, and may result in information of clinical importance regarding the therapeutic effects of drugs on disordered platelet function. Finally, these studies could provide the basis for the use of measurements of intracellular second messengers in clinical medicine.

许多全身性疾病都与身体机能异常有关。 血小板聚集和储存颗粒分泌，但 这种功能紊乱的生化基础尚不清楚。 这 这些研究的主要目的是评估异常 取自患有以下疾病的患者的血小板的刺激-反应耦合 血栓性心血管疾病，以确定其影响 对这些患者进行血小板治疗干预 功能，并评估细胞内变化的重要性 在以下条件下调节正常血小板的激活 模拟体内激活。 根据我们之前的体外研究 证明细胞内 Ca++ 与 血小板功能变化，我目前的工作假设是 1) 细胞质电离 (Ca++) 响应于一种 激动剂“启动”血小板以产生协同功能反应 额外的激动剂和 2) 血小板 Ca++ 异常 体内平衡可能是血栓功能改变的基础 心血管疾病。 由于水母发光蛋白和荧光探针 indo-1、quin2 和 fura-2 似乎测量不同方面 Ca++ 稳态，两者都将用于记录血小板中的 (Ca++) 受到各种物质的刺激或抑制。 在正常血小板中， 阈下浓度的个体和净效应 将比较几种激动剂以评估 Ca++ 在 协同作用。 两个指标所见的 Ca++ 瞬态将是 与其他血小板活化标志物相比，包括 纤维蛋白原结合和血小板蛋白磷酸化， 确定 (Ca++) 增加的生理相关性。 血将 也可以从缺血性心脏病患者身上获得 确定静息或刺激 Ca++ 是否发生变化或 Ca++ 与其他第二信使之间的关系是 这些疾病的特征。 Ca++ 异常将是 与尿毒症患者血小板中发现的结果相比， 这与出血时间延长有关 尚不清楚。 最后，一定的治疗效果 对缺血性心脏病患者的干预措施 经过测试，包括鱼油和 Ca++ 拮抗剂，以更好地 了解它们的作用机制。 这些研究应该 更好地了解血小板刺激反应 体内耦合，并可能产生临床信息 药物治疗作用的重要性 血小板功能紊乱。 最后，这些研究可以提供 使用细胞内第二测量的基础 临床医学的使者。