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

此K24修订版应用程序的目标是建立和加强研究和培训计划，重点是 研究认知老化的血管因素的机制和潜在的相关疗法， 阿尔茨海默病（AD）。关注患者导向研究（POR）这一领域的科学基础是 越来越多的全身和脑血管系统的改变被确定为风险因素， 可能参与与年龄相关的认知能力下降和痴呆（包括AD）的因果途径。 心血管疾病（CVD）和阿尔茨海默病（AD）有许多共同的风险因素，如高血压和 糖尿病一个共同的潜在统一假设是，CVD和AD都涉及内皮功能障碍， 影响多个脑过程的状态，如灌注、血流动力学调节、血脑屏障 渗透性、动脉粥样硬化进展和导致认知能力下降的免疫炎症途径， AD病理学从治疗的角度来看，血管紧张素受体阻滞剂（ARB）具有多效性， 内皮细胞和我过去几年的研究表明它有治疗潜力。我 根据本申请的职业目标是（a）建立一个以临床试验为重点的POR培训计划， 当前和未来资助的研究活动;（B）确定和培训临床和非临床研究人员， 特别是来自代表性不足的少数民族，有兴趣参与POR;以及（c）加强我的研究 技能-通过学习新的蛋白质组学方法和细胞生物学，用于开发AD临床生物标志物 审判和指导技能在POR。为了实现这些职业目标，我将利用出色的研究， 在埃默里大学的培训环境，并建立在一个强大的正在进行的和NIH资助的研究集（1队列 和2个活跃的临床试验），以体验方式学习和教授这些新技能。具体来说，我建议辅助 我的积极研究旨在：（d）验证在非靶向组织中发现的内皮蛋白质 在我正在进行的3项研究中，从个人收集的CSF中的蛋白质组学，并调查它们在 血管紧张素受体阻滞剂治疗1年;和（e）研究ARB对祖细胞的作用， 与AD相关，并进行初步研究以评估是否在外周血中使用scRNAseq（有和没有 药理学骨髓动员）揭示了这些细胞的不同功能。的成功 迄今为止，指导POR的临床医生和科学家以及强大而富有成效的研究活动确保了我 成功这个K24是我职业生涯中期的关键一步，最终实现了我的领导力和独立性目标。

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.