Mid-Career Program for Vascular Contributions to Alzheimer's disease

血管对阿尔茨海默氏病的影响的职业中期计划

• 批准号: 10343689
• 负责人: IHAB M HAJJAR
• 金额: $ 18.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343689
• 关键词: AMD3100; Active Learning; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-Protein; Ancillary Study; Angiotensin Receptor; Animals; Area; Autopsy; Biological Markers; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Bone Marrow; Brain; CD34 gene; CXCR4 gene; Cardiovascular Diseases; Cell Count; Cell physiology; Cells; Cellular biology; Clinical Sciences; Clinical Trials; Cognitive; Cognitive aging; Conduct Clinical Trials; Custom; Data; Dementia; Diabetes Mellitus; Dimensions; Discipline; Disease; Disease Marker; Educational Curriculum; Endothelium; Ensure; Environment; Exhibits; Failure; Funding; Future; Gene Expression; Goals; Health; Hypertension; Immune; Impaired cognition; Individual; Inflammatory; Investigation; Leadership; Learning; Link; Lisinopril; Measures; Mentors; Mentorship; Methods; Molecular; Molecular Analysis; Monitor; Neurosciences; Outcome; Participant; Pathway interactions; Perfusion; Pharmacology; Pilot Projects; Prevention; Process; Proteins; Proteomics; Reaction; Regulation; Renin-Angiotensin System; Research; Research Activity; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resources; Risk Factors; Role; Scientist; Testing; Therapeutic; Training; Training Activity; Training Programs; Translational Research; Underrepresented Minority; United States National Institutes of Health; Universities; Vascular System; Work; aging population; antagonist; base; biomarker development; blood-brain barrier permeabilization; career; cohort; endothelial stem cell; hemodynamics; in vivo; interest; mild cognitive impairment; novel; novel therapeutics; patient oriented research; peripheral blood; pleiotropism; potential biomarker; prodromal Alzheimer' s disease; programs; recruit; response biomarker; single-cell RNA sequencing; skills; stem cell function; stem cells; success; tau Proteins; transcriptomics; vascular contributions; vascular factor

The goal of this K24 revised application is to build and enhance a research and training program focusing on investigating mechanisms and potentially related therapies for vascular contributors to cognitive aging and Alzheimer’s disease (AD). The scientific basis for focusing on this area of Patient-Oriented Research (POR) is that increasingly, alterations in both systemic and brain vascular systems are being identified as risk factors and potentially involved in the causal pathway for both age-related cognitive decline and dementia, including AD. Cardiovascular disease (CVD) and Alzheimer’s disease (AD) share many risk factors, such as hypertension and diabetes. A common potentially unifying hypothesis is that both CVD and AD involve an endothelial dysfunctional state that affects multiple brain processes such as perfusion, hemodynamic regulation, blood-brain barrier permeability, atherosclerotic progression and immune-inflammatory pathways leading to cognitive decline and AD pathology. From a therapeutic perspective, angiotensin receptor blockers (ARB) have a pleiotropic effect on the endothelium and my studies conducted over the last few years suggest it has a therapeutic potential. My career aims under this application is to (a) establish a POR training program focused on clinical trials into my current and future funded research activities; (b) Identify and train clinician and non-clinician investigators, particularly from underrepresented minorities, interested in being engaged in POR; and (c) enhance my research skills- through learning new proteomic methods and cell biology for development of biomarkers in AD clinical trials, and mentorship skills in POR. To achieve these career goals, I will leverage an excellent research and training environment at Emory University and build on a robust ongoing and NIH-funded set of studies (1 cohort and 2 active clinical trials) to experientially learn and teach these new skills. Specifically, I propose ancillary studies to my active research that aim to: (d) validate endothelial-based proteins discovered in untargeted proteomics in the CSF collected from individuals in my ongoing 3 studies and investigate if they are altered after 1 year of angiotensin receptor blocker treatment; and (e) to investigate the effect of ARBs on progenitor cells, linked to AD, and perform a pilot study to assess if using scRNAseq on peripheral blood (with and without pharmacological bone marrow mobilization) reveals differential functions of these cells. The success in mentoring clinicians and scientists in POR to date and the robust and productive research activities ensures my success. This K24 is a critical step in my midcareer to ultimately reach my leadership and independence goals.

该K24修订应用程序的目标是建立和增强研究和培训计划，重点是 调查对认知衰老和血管促进者的机制和潜在相关疗法 阿尔茨海默氏病（AD）。关注这一面向患者研究领域（POR）的科学基础是 越来越多的系统性变化都被确定为风险因素和 可能涉及与年龄相关的认知下降和痴呆症（包括AD）的因果途径。 心血管疾病（CVD）和阿尔茨海默氏病（AD）具有许多危险因素，例如高血压和 糖尿病。一个常见的统一假设是CVD和AD都涉及内皮功能失调 影响多种大脑过程的状态，例如灌注，血液动力学调节，血脑屏障 渗透性，动脉粥样硬化进展和免疫炎症途径导致认知能力下降和 广告病理学。从治疗的角度来看，血管紧张素受体阻滞剂（ARB）对多效性影响 在过去的几年中，内皮和我的研究表明它具有治疗潜力。我的 在此应用下的职业目标是（a）建立一个专注于临床试验的POR培训计划 当前和未来资助的研究活动； （b）识别和培训临床和非临床研究者， 特别是来自代表性不足的少数民族，有兴趣参与POR； （c）增强我的研究 技能 - 学习新的蛋白质组学方法和细胞生物学，用于开发AD临床的生物标志物 试验和POR的心态技巧。为了实现这些职业目标，我将利用一项出色的研究和 埃默里大学的培训环境，并建立在坚固且NIH资助的一组研究的基础上（1个队列 和2项活跃的临床试验）熟练地学习和教授这些新技能。具体来说，我建议辅助 对我的积极研究的研究，目的是：（d）验证基于内皮的蛋白质在不靶向的情况下发现 在我正在进行的3项研究中，从个体收集的CSF中的蛋白质组学，并调查它们是否在 1年血管紧张素受体阻滞剂治疗； （e）研究ARB对祖细胞的影响， 与AD相关，并进行试验研究以评估是否在外周血上使用scrnaseq（有和没有 药理学骨髓动员）揭示了这些细胞的差异功能。成功 迄今为止，POR的指导临床医生和科学家以及强大的产品研究活动可确保我 成功。这款K24是我的中级护理人员最终达到我的领导和独立目标的关键一步。