Pathway maps of platelet phenotype and function

血小板表型和功能的通路图

• 批准号: 10284852
• 负责人: JOSEPH E ASLAN
• 金额: $ 37.66万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284852
• 关键词: Acute; Adhesions; Administrative Supplement; Affect; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease related dementia; Atherosclerosis; Award; Blood Cells; Blood Platelets; Blood Vessels; Cells; Chronic; Clinic; Coagulation Process; Cognition; Collaborations; Diagnosis; Diagnostic; Disease; Disease Progression; Endothelium; Etiology; Event; Goals; Health; Hemorrhage; Hemostatic function; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Maps; Measures; Methods; Molecular; Oregon; Parents; Pathology; Pathway interactions; Physiological; Prevention strategy; Proteomics; Research; Research Personnel; Signal Transduction; System; Thrombosis; Vascular Diseases; Work; base; improved; mild cognitive impairment; multidisciplinary; platelet function; platelet phenotype; prevent; programs; ranpirnase; response; sex; therapeutically effective; thrombotic; tool; vascular inflammation

ABSTRACT FOR ADMINISTRATIVE SUPPLEMENT Platelets are specialized peripheral blood cells that rapidly engage and resolve endothelial injury through adhesion, secretion and aggregation responses. These regulated changes in platelet form and function are essential to hemostasis and vascular health, but also support acute and chronic pathologies of aging (i.e., thrombosis, atherosclerosis).Translational efforts aiming to determine disease-specific platelet activities have identified heterogeneous platelet phenotypes in the laboratory as well as in the clinic associated with acute thrombotic and chronic inflammatory conditions – including vascular pathologies in Alzheimer’s disease and related dementias (AD/ADRD). The mechanisms by which maladaptive platelet phenotypes arise in disease are unclear. Efforts to develop effective therapeutic, diagnostic and preventive strategies focused on maladaptive platelets in aging and vascular diseases remain to be actualized. In this Administrative Supplement, we aim to determine how Alzheimer’s disease etiology relates to alterations in molecular programs of platelets that support inflammatory and thrombotic responses associated with disease. Our central hypothesis is that signaling systems underlying platelet cell physiological responses are specifically dysregulated in Alzheimer’s disease in a manner promoting as well as marking disease progression. As a supplement to our parent award, this study will make further use of a high-throughput, proteomics-based workflow to measure and map intracellular signaling events in platelets isolated from donors with Alzheimer’s disease relative to platelets from age and sex matched mild cognitive impairment (MCI) and normal cognition (NC) control donors. In collaboration with clinicians and researchers from the NIA P30-supported Oregon Alzheimer’s Disease Center (OADC), our multidisciplinary team will systematically define how Alzheimer’s disease relates to alterations in intracellular signaling events that orchestrate platelet adhesion (Aim 1), secretion (Aim 2) and aggregation (Aim 3) in the context of vascular inflammation and Alzheimer’s disease progression. As a major goal of the parent award is to determine how maladaptive platelet phenotypes develop, and, ultimately, how they may be targeted and managed, this Supplement provides a unique opportunity to add value to ongoing studies while advancing Alzheimer’s disease research with state-of-the-art methods. Ultimately, this work will generate knowledge as well as a conceptual means to understand how to better predict, detect and manage Alzheimer’s disease.

行政补充摘要 血小板是一种特殊的外周血细胞，可通过以下方式快速参与并解决内皮损伤： 粘附、分泌和聚集反应。血小板形式和功能的这些调节变化是 对于止血和血管健康至关重要，而且还支持急性和慢性衰老病理（即， 血栓形成、动脉粥样硬化）。旨在确定疾病特异性血小板活性的转化努力已取得进展 在实验室和临床中鉴定出与急性血小板相关的异质性血小板表型 血栓和慢性炎症——包括阿尔茨海默氏病和 相关痴呆症（AD/ADRD）。疾病中出现适应不良血小板表型的机制 不清楚。努力制定有效的治疗、诊断和预防策略，重点关注 血小板在衰老和血管疾病中的适应不良仍有待实现。在本行政 作为补充，我们的目标是确定阿尔茨海默病的病因学与分子改变之间的关系 支持与疾病相关的炎症和血栓反应的血小板程序。我们的中央 假设是血小板细胞生理反应的信号系统是特定的 阿尔茨海默病中的失调以促进和标记疾病进展的方式。作为一个 作为对我们家长奖的补充，这项研究将进一步利用高通量、基于蛋白质组学的方法 测量和绘制从患有阿尔茨海默病的捐赠者身上分离的血小板中的细胞内信号转导事件的工作流程 年龄和性别与血小板相关的疾病与轻度认知障碍 (MCI) 和正常认知相匹配 (NC) 对照捐赠者。与 NIA P30 支持的俄勒冈州临床医生和研究人员合作 阿尔茨海默病中心 (OADC)，我们的多学科团队将系统地定义阿尔茨海默病如何 疾病与协调血小板粘附的细胞内信号传导事件的改变有关（目标 1）， 血管炎症和阿尔茨海默病背景下的分泌（目标 2）和聚集（目标 3） 进展。家长奖的一个主要目标是确定适应不良的血小板表型如何 开发，以及最终如何定位和管理它们，本补充提供了独特的 有机会为正在进行的研究增加价值，同时利用最先进的技术推进阿尔茨海默病研究 方法。最终，这项工作将产生知识以及理解如何 更好地预测、检测和管理阿尔茨海默病。