Pathway maps of platelet phenotype and function

行政解释摘要 血小板是特化的外周血细胞，其通过以下途径快速接合并解决内皮损伤： 粘附、分泌和聚集反应。血小板形态和功能的这些受调节的变化是 对于止血和血管健康是必需的，而且还支持急性和慢性衰老病理（即， 旨在确定疾病特异性血小板活性的转化努力已经 在实验室和临床中发现了与急性血小板减少性紫癜相关的异质性血小板表型， 血栓形成和慢性炎性病症-包括阿尔茨海默病中的血管病变， 相关性痴呆（AD/ADRD）。疾病中出现适应不良血小板表型的机制 不清楚。制定有效的治疗、诊断和预防战略的努力侧重于 血小板在衰老和血管疾病中的适应不良仍有待实现。本行政 补充，我们的目标是确定阿尔茨海默病的病因如何与分子水平的改变有关。 血小板的程序，支持炎症和血栓反应与疾病有关。我们的中央 假设是血小板细胞生理反应的信号系统是特异性的， 在阿尔茨海默氏病中以促进和标记疾病进展的方式失调。作为 作为对我们父母奖励的补充，这项研究将进一步利用高通量，基于蛋白质组学的 测量和绘制从阿尔茨海默病供体分离的血小板中的细胞内信号传导事件的工作流程 与年龄和性别匹配的轻度认知障碍（MCI）和正常认知相关的疾病 (NC)对照供体。与来自NIA P30支持的俄勒冈州的临床医生和研究人员合作， 阿尔茨海默氏病中心（OADC），我们的多学科团队将系统地定义阿尔茨海默氏症如何 疾病涉及协调血小板粘附的细胞内信号传导事件的改变（Aim 1）， 血管炎症和阿尔茨海默病背景下的分泌（目的2）和聚集（目的3） 进展作为父母奖的一个主要目标是确定适应不良的血小板表型 发展，并最终，如何可能有针对性和管理，本补充提供了一个独特的 有机会为正在进行的研究增加价值，同时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，以及一个概念性的手段，以了解如何 更好地预测、检测和管理阿尔茨海默病。

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.