Juvenile Protective Factor Deficits in Endothelial Aging, Dysfunction and Disease

内皮衰老、功能障碍和疾病中的青少年保护因子缺陷

基本信息

批准号：
7919068
负责人：
Victoria L Herrera
金额：
$ 15.29万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919068
关键词：
Acute Kidney Failure Address Adhesions Adolescent Adult Age Aging Animal Disease Models Anti-Inflammatory Agents Anti-inflammatory Antibodies Area Atherosclerosis Attenuated Autologous Blood Platelets Cardiovascular Diseases Cardiovascular system Categories Cell Therapy Cells Cerebrovascular Disorders Characteristics Clinical Research Complex Coronary Arteriosclerosis Coronary heart disease Data Development Diabetes Mellitus Disease Disease Progression Disease susceptibility DsRed Endothelial Cells Endothelium Equilibrium Etiology Female Fluorescence Functional disorder Future Gender Genes Genetic Predisposition to Disease Goals Hand Health Heart Diseases Homing Hyperlipidemia Hypertension Impairment In Vitro Individual Injury Intervention Investigation Label Lead Maintenance Mediating Modeling Molecular Profiling Morbidity - disease rate Myocardial Infarction Organ Oxidative Stress Pathogenesis Pathology Pathway Analysis Pathway interactions Phenotype Platelet Transfusion Play Predisposition Preventive Intervention Proteome Proteomics Rat Transgene Rattus Regulation Rejuvenation Research Resistance Risk Factors Role Side Signal Transduction Signaling Molecule Spleen Staging Stem cells Stroke Technology Telomere Shortening Testing Time Time Factors Transfusion Transgenic Organisms Transplanted Lung Complication Treatment Efficacy Vascular Diseases Vascular Endothelium Vasomotor age effect aged attenuation base caveolin 1 cell motility comparative disorder risk enhanced green fluorescent protein hypertensive heart disease in vivo injury and repair insight male migration mortality multiple reaction monitoring oxidative DNA damage peripheral blood promoter protein expression repaired research study salt sensitive sex tool von Willebrand Factor young adult

项目摘要

DESCRIPTION (provided by applicant): In accordance with RFA-AG-08-003, our long term goal is to define juvenile protective factors that protect the endothelium in the young, but are lost or altered with aging, and further compromised in the presence of genetic susceptibility to cardio- and cerebro-vascular disease. Emerging research data and our own preliminary data pinpoint two candidate juvenile protective factors: 1) endothelial progenitor cells (EPCs) and 2) platelets (plts). While their normal interactions suggest a pathway for synergistic repair mechanisms on the one hand, their dysfunctional interactions delineate a pathway for synergistic pathogenic mechanisms. Capitalizing on our transgenic rat model of coronary atherosclerosis with male susceptibility, and rat stroke model with increased female-susceptibility, and validated experimental tools and technologies, we prioritize the following Aims in the investigation of EPCs and platelets as two interacting candidate juvenile protective factors. Aim 1. Identification of EPC- and platelet-characteristics that define them as "juvenile protective factors", the time point at which the phenotype switch to "aged EPCs" occur, and the impact gender and disease susceptibility have on the "juvenile protective cellular and functional profile" of EPCs and platelets. Aim 2. Identify gene-networks involved in the switch in EPCs and platelets from 'juvenile protective factors' to 'aging-deficient factors', in order to pinpoint targets for "rejuvenation of aged EPCs" and address feasibility of "rejuvenation and subsequent transfusion" of autologous EPCs. This will be done by determining gene- pathway changes associated with maturational and aging changes in EPCs and platelets by targeted comparative proteomics using multiple reactions monitoring, and by signaling antibody (ab)-array profiling assessing constitutive changes in signaling molecules. Targeted pathway analysis will focus on gene networks involved in EPC-mediated endothelial repair and EPC-platelet interactions, and those implicated in EPC dysfunction. Aim 3. Provide proof of concept for juvenile protective factor-based intervention for cardiovascular and cerebrovascular disease by determining effects of in vivo transfusion of juvenile EPCs and platelets on disease progression of coronary heart disease and stroke in validated transgenic rat models of CAD (Tg25- cad) and stroke (Tg25-sp). Proposed studies will provide insight into i) the roles of EPCs, platelets and EPC- platelet complexes as candidate juvenile protective factors, ii) identify pathways for "rejuvenation of aged EPCs and/or platelets", and importantly, iii) provide proof-of-concept of juvenile-factor based intervention efficacy in the maintenance/repair of vascular endothelium. Information to be obtained will provide insight into the roles of endothelial repair mechanisms in attenuating cardiovascular and cerebrovascular disease mechanisms and target organ complications. We propose to study endothelial progenitor cells (EPCs) and EPC-platelet complexes as candidate juvenile protective factors which are critical for endothelial health but are lost with aging, and in heart disease and stroke. Through the use of transgenic rat models of heart disease and stroke, we will investigate how EPCs are altered with age, by sex-specific differences, and by genetic susceptibility to hypertension, heart disease and stroke in terms of their cell subtypes, proteome, signaling cascades. Knowing how they differ, we will then transfuse best candidates to see if they can alter hypertension, heart disease or stroke in corresponding rat models, thereby providing proof of concept for future clinical studies.

描述（由申请人提供）：根据 RFA-AG-08-003，我们的长期目标是定义幼年保护因子，这些因子可以保护年轻人的内皮细胞，但会随着衰老而丢失或改变，并在存在时进一步受到损害心脑血管疾病的遗传易感性。新兴研究数据和我们自己的初步数据确定了两种候选青少年保护因子：1) 内皮祖细胞 (EPC) 和 2) 血小板 (plts)。虽然它们的正常相互作用一方面表明了协同修复机制的途径，但它们功能失调的相互作用描绘了协同致病机制的途径。利用我们的雄性易感性冠状动脉粥样硬化转基因大鼠模型和女性易感性增加的大鼠中风模型，以及经过验证的实验工具和技术，我们在研究 EPC 和血小板作为两个相互作用的候选青少年保护因子时优先考虑以下目标。目标 1. 鉴定将 EPC 和血小板定义为“幼年保护因子”的特征、表型转变为“老年 EPC”的时间点，以及性别和疾病易感性对“幼年保护细胞”的影响EPC 和血小板的功能概况”。目标2. 识别EPCs和血小板从“幼年保护因子”向“衰老缺陷因子”转变的基因网络，从而确定“衰老EPCs返老还童”的靶点并解决“返老还童随后输血”的可行性“自体EPC。这将通过使用多重反应监测的有针对性的比较蛋白质组学来确定与 EPC 和血小板的成熟和衰老变化相关的基因途径变化，并通过信号抗体 (ab) 阵列分析评估信号分子的组成性变化来完成。靶向通路分析将重点关注参与 EPC 介导的内皮修复和 EPC-血小板相互作用的基因网络，以及与 EPC 功能障碍有关的基因网络。目标 3. 通过确定体内输注幼年 EPC 和血小板对经过验证的 CAD 转基因大鼠模型 (Tg25- CAD）和中风（Tg25-sp）。拟议的研究将深入了解 i) EPC、血小板和 EPC-血小板复合物作为候选青少年保护因子的作用，ii) 确定“老化 EPC 和/或血小板的复兴”途径，重要的是，iii) 提供证据-血管内皮维持/修复中基于幼年因子的干预功效的概念。获得的信息将有助于深入了解内皮修复机制在减轻心脑血管疾病机制和靶器官并发症中的作用。我们建议研究内皮祖细胞 (EPC) 和 EPC-血小板复合物作为候选幼体保护因子，它们对内皮健康至关重要，但会随着衰老、心脏病和中风而丢失。通过使用心脏病和中风的转基因大鼠模型，我们将研究EPC如何随着年龄、性别差异以及对高血压、心脏病和中风的遗传易感性在细胞亚型、蛋白质组、信号传导方面发生变化。级联。了解它们有何不同后，我们将输注最佳候选者，看看它们是否可以在相应的大鼠模型中改变高血压、心脏病或中风，从而为未来的临床研究提供概念证明。