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.

摘要行政补充 血小板是专门的外围血细胞，通过 粘附，分泌和聚集反应。这些调节的血小板形式和功能的变化是 对于止血和血管健康至关重要，但也支持衰老的急性和慢性病理（即 血栓形成，动脉粥样硬化。 在实验室以及与急性相关的诊所中鉴定出异质的血小板表型 血小板和慢性炎症状况 - 包括阿尔茨海默氏病和 相关痴呆症（AD/ADRD）。疾病中不良适应性血小板表型的机制 不清楚。制定有效的治疗，诊断和预防策略的努力 衰老和血管疾病中的适应不良血小板仍有待实现。在此管理中 补充，我们旨在确定阿尔茨海默氏病的病因与分子变化的关系如何 支持与疾病相关的炎症和血小板反应的血小板计划。我们的中心 假设是血小板细胞物理反应的基础信号系统是专门的 在阿尔茨海默氏病中失调的方式促进并标记疾病进展。作为 补充我们的父母奖，这项研究将进一步使用高通量，基于蛋白质组学 从阿尔茨海默氏症供体分离的血小板中测量和映射细胞内信号事件的工作流程 疾病相对于年龄和性别匹配的轻度认知障碍（MCI）和正常认知的疾病 （NC）控制供体。与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 疾病与编排血小板粘合剂的细胞内信号传导事件的改变（AIM 1）， 在血管注射和阿尔茨海默氏病的背景下，分泌（目标2）和聚集（目标3） 进展。作为父母奖的主要目标是确定适应不良的血小板表型 开发，最终，如何将它们成为目标和管理，该补充提供了独特的 有机会为正在进行的研究增加价值，同时通过最先进的 方法。最终，这项工作将产生知识和概念手段，以了解如何 更好地预测，检测和管理阿尔茨海默氏病。