Signal transduction defects in human platelets

人血小板的信号转导缺陷

• 批准号: 6570522
• 负责人: Angara Koneti Rao
• 金额: $ 20.93万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570522
• 关键词: biological signal transduction; calcium flux; clinical research; guanine nucleotide binding protein; human subject; molecular pathology; phospholipase C; phosphorylation; platelet activation; platelet disorder

Platelets play a major role in hemostasis in congenital defects in platelet function are associated with bleeding manifestations. The goal of this project is to define the biochemical mechanisms underlying the platelet dysfunction in patients with congenital platelet function defects and thereby enhance our understanding of the normal platelet activation mechanisms, which are vital to the development of newer therapeutic strategies for both bleeding and thrombotic disorders. The vast majority of patients with congenital platelet defects are generally characterized by impaired aggregation responses and dense granule secretion on activation; most of them have normal dense granule stores. These patients are lumped in the loosely defined group called "platelet secretion defects" or "activation defects". In them, the underlying biochemical and molecular mechanisms are totally unknown. Our hypothesis is that these patients have defects in the signal transduction mechanisms This project focuses on specific patients in whom we demonstrate hitherto undescribed deficiencies in two major proteins involved in signal transduction mechanisms, namely, a) phospholipase C-beta2 (Aim 1), and b) GTP- binding protein Galphaq (Aim 2), respectively. Our studies to date demonstrate that the coding sequence of PLC-beta2 and Galphaq gene is normal in these patients but the respective mRNA levels are decreased. We will study the transcriptional regulation of PLC-beta2 (Aim 1) and Galphaq (Aim 2) to define the mechanisms. In several other patient with platelet function defects, we have obtained evidence for abnormalities in the signaling events (e.g. Ca2+ mobilization, pleckstrin phosphorylation). In Aim 3, we will perform detailed studies in 3-4 patients and their family members to characterize the mechanisms leading to the impaired responses. This project represents application of state-of-the-art techniques to define the molecular mechanisms of platelet dysfunction in a group of patients who are very poorly characterized at present and constituted an untapped source of new information. These studies will provide new information on the role of two major protein, PLC-beta2 and Galphaq, in platelet signal transduction mechanisms.

血小板在血小板功能的先天性缺陷中在止血中起主要作用，与出血表现有关。该项目的目的是定义先天性血小板功能缺陷患者血小板功能障碍的生化机制，从而增强我们对正常血小板活化机制的理解，这对于出血和血栓形成疾病的新治疗策略至关重要。绝大多数先天性血小板缺陷的患者通常以聚集反应受损和激活的致密颗粒分泌为特征。他们中的大多数都有正常的密集颗粒店。这些患者在宽松定义的组中，称为“血小板分泌缺陷”或“激活缺陷”。在其中，潜在的生化和分子机制是完全未知的。我们的假设是，这些患者在信号转导机制中具有缺陷，该项目的重点是在其中证明迄今未描述的两个主要蛋白质中未描述的缺乏，参与信号转导机制，即a）磷脂酶C-beta2（AIM 1）（AIM 1），以及B）GTP-GTP-结合蛋白质protein Galphaq（AIM 2），迄今为止，我们的研究表明，PLC-BETA2和GALPHAQ基因的编码序列在这些患者中是正常的，但各自的mRNA水平降低。我们将研究PLC-BETA2（AIM 1）和Galphaq（AIM 2）的转录调控以定义机制。在其他几名患有血小板功能缺陷的患者中，我们获得了信号事件异常（例如CA2+动员，Pleckstrin磷酸化）的证据。在AIM 3中，我们将对3-4名患者及其家人进行详细研究，以表征导致反应受损的机制。该项目代表了最先进的技术来定义一组非常差的患者中血小板功能障碍的分子机制，这些患者目前表征较差，构成了未开发的新信息来源。这些研究将提供有关两种主要蛋白PLC-BETA2和Galphaq在血小板信号转导机制中的作用的新信息。