Glutamate Mediates Platelet Activation through an Ionotropic Glutamate Receptor

谷氨酸通过离子型谷氨酸受体介导血小板激活

• 批准号: 8065694
• 负责人: CRAIG N MORRELL
• 金额: $ 38.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065694
• 关键词: AMPA Receptors; Acids; Agonist; Biological Assay; Bleeding time procedure; Blood Coagulation Factor; Blood Platelets; Cardiovascular Diseases; Cause of Death; Cells; Cellular Structures; Complex; Data; Development; Endothelial Cells; Event; Flow Cytometry; G Protein-Coupled Receptor Genes; Glutamate Receptor; Glutamates; Journals; Kainic Acid; Kainic Acid Receptors; Kinetics; Measurement; Mediating; Medicine; Membrane; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Ischemia; NCOA2 gene; Neurons; Paper; Patch-Clamp Techniques; Pathway interactions; Physiological; Platelet Activation; Platelet Inhibitors; Platelet aggregation; Play; Prevention; Process; Publishing; Receptor Activation; Receptor Signaling; Regulation; Reperfusion Injury; Reporting; Role; Signal Transduction; Stroke; Synapses; Testing; Therapeutic Intervention; Thrombosis; Vascular Diseases; World Health; acute coronary syndrome; atherothrombosis; cell type; extracellular; in vivo; mortality; neurotransmitter release; novel; public health relevance; receptor

DESCRIPTION (provided by applicant): Cardiovascular disease and stroke are major causes of morbidity and mortality. Although many pathophysiological processes play a role in the development of vascular disease, thrombosis often is the event that precipitates stroke and acute coronary syndromes. Many platelet receptors and activation pathways are conserved in other cell types, including neurons. Platelets release the neurotransmitter glutamate during activation, but the role of glutamate signaling in the vasculature is unknown. We have discovered that platelets express ionotropic glutamate receptors, including the AMPA type receptor (AMPAR) and the Kainic Acid (KA) type receptor (KAR). Furthermore, we demonstrate that AMPA and KA receptor signaling increase platelet activation. We hypothesize that platelets express functional glutamate sensitive complexes that increase agonist induced platelet activation and thrombosis. To explore this hypothesis, we propose the following Specific Aims: Specific Aim 1: To define the mechanisms of glutamate mediated increase in agonist induced platelet activation. We will extend our extensive Preliminary Data to further explore the regulation of platelet activation by ionotropic glutamate receptors. Using flow cytometry, platelet aggregation, and whole cell patch clamp techniques we will further dissect platelet glutamate signaling. Specific Aim 2: To define platelet glutamate receptor accessory molecule interactions. Aim 2 will focus on the molecular machinery that facilitates AMPAR and KAR membrane localization and stability in platelets. Specific Aim 3: To demonstrate that glutamate signaling promotes thrombosis and ischemia-reperfusion injury. To further explore glutamate regulation of platelet function we will use in vivo measurements of platelet function, including bleeding time and thrombosis. We will also demonstrate the importance of the promotion of platelet activation by AMPAR and KAR using a model of ischemia- reperfusion injury. PUBLIC HEALTH RELEVANCE: In 2001, a World Health Report noted atherothrombosis (ischemic heart disease and stroke) to be the leading cause of death worldwide. Platelets have a prominent role in cardiovascular disease and platelet inhibitors are a main therapeutic intervention. The proposed study will help elucidate novel targets for the development of new therapies in the prevention and treatment of cardiovascular disease.

描述（由申请人提供）：心血管疾病和中风是发病率和死亡率的主要原因。尽管许多病理生理过程在血管疾病的发展中起作用，但血栓形成通常是沉淀中风和急性冠状动脉综合征的事件。许多血小板受体和激活途径在包括神经元在内的其他细胞类型中保守。血小板在激活过程中释放神经递质谷氨酸，但是谷氨酸信号在脉管系统中的作用尚不清楚。我们发现血小板表达离子型谷氨酸受体，包括AMPA型受体（AMPAR）和Kainic Acid（KA）型受体（KAR）。此外，我们证明AMPA和KA受体信号传导增加了血小板激活。我们假设血小板表达功能性谷氨酸敏感复合物，从而增加了激动剂诱导的血小板激活和血栓形成。为了探讨这一假设，我们提出了以下特定目的：特定目的1：定义谷氨酸介导的机制介导的激动剂诱导的血小板激活的增加。我们将扩展广泛的初步数据，以进一步探索离子型谷氨酸受体对血小板激活的调节。使用流式细胞仪，血小板聚集和全细胞贴片夹技术，我们将进一步剖析血小板谷氨酸信号传导。特定目的2：定义血小板谷氨酸受体辅助分子相互作用。 AIM 2将集中在促进AMPAR和KAR膜定位和血小板中的稳定性的分子机械上。特定目的3：证明谷氨酸信号传导促进血栓形成和缺血 - 再灌注损伤。为了进一步探索血小板功能的谷氨酸调节，我们将在血小板功能的体内测量中使用，包括出血时间和血栓形成。我们还将使用缺血再灌注损伤模型来证明AMPAR和KAR促进血小板激活的重要性。公共卫生相关性：2001年，一份世界卫生报告指出，动脉粥样硬化（缺血性心脏病和中风）是全球死亡的主要原因。血小板在心血管疾病中具有重要作用，血小板抑制剂是主要的治疗干预措施。拟议的研究将有助于阐明在预防和治疗心血管疾病的新疗法方面的新靶标。