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.

此K24修订应用程序的目标是建立和加强研究和培训计划，重点是 研究血管因素导致认知老化的机制和潜在的相关治疗 阿尔茨海默病(AD)。专注于这一领域以患者为中心的研究(POR)的科学基础是 越来越多地，全身和脑血管系统的改变被确定为危险因素和 可能与年龄相关的认知衰退和痴呆症(包括阿尔茨海默病)的因果关系有关。 心血管疾病(CVD)和阿尔茨海默病(AD)具有许多共同的危险因素，如高血压和 糖尿病。一个常见的潜在统一假设是，CVD和AD都与内皮功能障碍有关 影响多个脑过程的状态，如灌注、血流动力学调节、血脑屏障 通透性、动脉粥样硬化进展和免疫炎症途径导致认知功能下降和 公元病理学。从治疗的角度来看，血管紧张素受体阻滞剂(ARB)对 内皮和我在过去几年中进行的研究表明，它具有治疗潜力。我的 此申请下的职业目标是：(A)建立以临床试验为重点的POR培训计划 目前和未来资助的研究活动；(B)确定和培训临床医生和非临床医生调查人员， 特别是来自代表人数不足的少数群体，有兴趣参与POR；和(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在AD临床中开发生物标记物 POR方面的试验和指导技能。为了实现这些职业目标，我将利用出色的研究和 埃默里大学的培训环境，并建立在强大的、正在进行的和NIH资助的一系列研究的基础上(1个队列 和2项积极的临床试验)，以经验地学习和传授这些新技能。具体来说，我建议辅助性的 对我的积极研究的研究旨在：(D)验证在非靶标中发现的基于内皮的蛋白质 在我正在进行的3项研究中收集的脑脊液中的蛋白质组学，并调查它们是否在 血管紧张素受体阻滞剂治疗1年；及(E)研究ARB对祖细胞的影响， 与AD有关，并进行一项试点研究，以评估是否在外周血中使用scRNAseq(有无 药理学骨髓动员)揭示了这些细胞的不同功能。在中国取得的成功 到目前为止，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的 成功。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目标。