ABNORMALITIES OF PLATELET CALCIUM IN DISEASE

疾病中血小板钙异常

• 批准号: 3471337
• 负责人: J Anthony Ware
• 金额: $ 7.26万
• 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/3471337
• 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.

许多系统性疾病与异常有关 血小板聚集和存储颗粒分泌，但 该无序功能的生化基础尚不清楚。 这 这些研究的主要目的是评估异常 从患者的血小板的刺激反应耦合 血栓性心血管疾病，以确定 这些患者在血小板上给予的治疗干预措施 功能，并评估细胞内变化的重要性 调节器在条件下激活正常血小板 模拟体内激活。 根据我们以前的体外研究 证明细胞内Ca ++和 血小板功能变化，我目前的工作假设是 1）响应一个细胞质离子化（Ca ++）的增加 激动剂“素数”的血小板协同功能响应 到其他激动剂和2）血小板Ca ++异常 稳态可能是血栓形成功能改变的基础 心血管疾病。 由于Aequorin和荧光探针 Indo-1，Quin2和Fura-2似乎测量了 Ca ++稳态，两者都将用于在血小板中记录（Ca ++） 由各种代理刺激或抑制。 在普通血小板中 亚阈值浓度的个体和净影响 将比较几种激动剂，以评估Ca ++在 协同作用。 Ca ++瞬变，这两个指标都将是 与血小板激活的其他标记相比 血小板蛋白的纤维蛋白原结合和磷酸化与 确定增加（Ca ++）的生理相关性。 血会 也可以从缺血性心脏病的患者中获得 确定静止或刺激的Ca ++的改变或 CA ++和其他第二使者之间的关系是 这些疾病的特征。 CA ++异常将是 与尿毒症患者的血小板中发现的那些相比 由于原因，这与长时间的出血时间有关 这还不清楚。 最后，某些治疗的作用 对缺血性心脏病患者的干预将是 测试，包括鱼油和Ca ++拮抗剂，以更好 了解他们的行动机制。 这些研究应该 提供对血小板刺激反应的更多了解 体内耦合，可能会导致临床信息 关于药物对治疗作用的重要性 血小板功能无序。 最后，这些研究可以提供 使用细胞内第二个测量的基础 临床医学的使者。