A Precision Medicine Approach To Study Targetable Pathways in Vascular Dementia

Elahi博士是一名职业生涯早期的内科医生兼科学家，曾接受过神经退行性疾病和 在生物标记物开发方面的经验，她寻求在退伍军人管理局发展她的职业生涯。通过结合她的临床 和分子生物学培训，Elahi博士的长期目标是帮助更好地了解 神经退行性疾病的血管通路，以提高早期诊断和 疾病修正疗法的发展将改变许多人的认知轨迹 患有血管疾病并有患痴呆症风险的个人。为了实现这一目标，伊拉希博士 寻求额外的培训，以发展她在两个主要领域的知识和技能：(1)医学领导力， 通过在退伍军人管理局和加州大学旧金山分校开设专门的诊所，评估来自各种原因的VCID退伍军人， 高系统性血管疾病/风险、中风、脑外伤、自身免疫性疾病和神经退行性疾病 (2)提高她在多模式数据驱动方面的科学技能 无偏生物标记物发现的分析方法。 为了更好地理解VCID，我们需要新的工具来处理人类疾病的复杂性 以及基于人类的生物和临床数据的噪声性质。因此，新的途径和方法 都是需要的。作为一名内科科学家，伊拉希博士是唯一适合追求前沿方法的人 VCID的诊断进展。然而，有了临床培训和责任，她还没有 获得对无偏见生物标志物发现项目的充分知识的机会，也不是重要的 有机会发展她在高级数据驱动分析方面的技能。 在这项申请中，Elahi博士建议使用她在神经退行性疾病和 在外体技术方面的技术专长，以对以下方面的贡献进行假设驱动建模 血管内皮细胞炎症和致病血管生成对脑部不良临床和放射学结果的影响 VCID(目标1和2)。而在Aim 3，与她的退伍军人管理局导师弗格森博士合作，她将第一次 《时代周刊》承担多维数据的分析，包括外体蛋白质组学、脑成像、视网膜 影像、临床变量和认知评分。拟议的工作范围与伊拉希博士的 目标是成为翻译VCID研究领域的领导者。假设和数据驱动的目标将提供 神经退行性疾病领域前沿研究的免费方法。这一目标将 提供以数据为驱动的离散临床生物标记物内表型发现的机会 在一群不同的受试者中。 这项研究有望促进对VCID诊断和治疗的了解 并为Elahi博士在VCID研究中的精确医学方法方面的领导做好准备。为确保成功， 这项工作的科学和培训目标，伊拉希博士组建了一支世界级的血管领域领导者团队 神经学和神经科学(Swanson)、神经退行性疾病(Miller)、神经学数据科学 疾病(弗格森)，以及以下领域的顾问/合作者：易感人群的流行病学和病因 VCID的推理(Gymour)、多模式神经成像(ROSEN)和认知(Kramer)。伊拉希博士的训练 将包括与她的导师和科学顾问的个人教程、实践经验、 和正式的课程作业。这项拟议的研究将为Elahi博士提供更大规模的前瞻性研究数据 不同病因的退伍军人人群中的微血管疾病：慢性和急性心血管疾病相关 系统性血管风险、脑外伤和自身免疫/炎症性疾病。她将提出一项功绩评估 在CDA期限结束前提交的申请。伊拉希博士热心致力于改善 通过研究了解退伍军人的认知和心理健康，并通过她提出的项目和培训，她将 在退伍军人事务部制定一个欣欣向荣的VCID研究项目。

Dr. Elahi is an early career physician-scientist with specialty training in neurodegenerative disease and experience in biomarker development, who seeks to develop her career at the VA. By combining her clinical and molecular biology training, Dr. Elahi's long-term goal is to contribute to a better understanding of vascular pathways in neurodegenerative disorders in order to improve early diagnoses and development of disease-modifying treatments that will alter the cognitive trajectory of so many individuals affected with vascular disease and at risk of dementia. In order to achieve this goal, Dr. Elahi seeks additional training to develop her knowledge and skills in two major domains: (1) leadership in medicine, by starting a specialized clinic at the VA and UCSF, to evaluate veterans with VCID from a variety of causes, high systemic vascular disease / risk, strokes, TBI, auto-immune disease, and neurodegenerative disease and to undertake their enrollment into research, (2) advancement of her scientific skills in multi-modal data-driven analytical approaches for unbiased biomarker discovery. To better understand VCID, we need novel tools that can handle both the complexity of human disease as well as the noisy nature of human-based biological and clinical data. Thus, novel approaches and methods are needed. As a physician-scientist, Dr. Elahi is uniquely suited to pursue cutting-edge approaches to advancement of diagnostics in VCID. However, with clinical training and responsibilities, she has not had the opportunity to acquire adequate knowledge of unbiased biomarker discovery projects, nor the important opportunity to develop her skills in advanced data-driven analytics. In this application, Dr. Elahi proposes to use her clinical expertise in neurodegenerative disease and technical expertise in exosomal technologies to undertake hypothesis-driven modelling of contributions of endothelial inflammation and pathogenic angiogenesis to adverse clinical and radiographic brain outcomes in VCID (Aims 1 and 2). While in Aim 3, in collaboration with her VA mentor, Dr. Ferguson, she will for the first time undertake the analysis of multi-dimensional data, including exosomal proteomics, brain imaging, retinal imaging, clinical variables and cognitive scores. The scope of the work proposed is aligned with Dr. Elahi’s goal of becoming a leader in translational VCID research. The hypothesis and data-driven aims will provide complimentary approaches to cutting-edge research in the field of neurodegenerative disease. This Aim will provide the opportunity to undertake data-driven discovery of discrete clinical-biomarker endophenotypes within a heterogenous cohort of subjects. This research is expected to advance understanding of VCID with diagnostic and therapeutic relevance and prepare Dr. Elahi for leadership in precision medicine approaches in VCID research. To ensure success of the scientific and training goals of this work, Dr. Elahi has assembled a world-class team of leaders in vascular neurology and neuroscience (Swanson), neurodegenerative disease (Miller), data science in neurological disease (Ferguson), and advisors/collaborators in: epidemiology of vulnerable populations and causal inference (Glymour), mutli-modal neuroimaging (Rosen), and cognition in VCID (Kramer). Dr. Elahi’s training will involve a combination of individual tutorials with her mentors and scientific advisors, hands-on experience, and formal coursework. The proposed research will provide Dr. Elahi with data for a larger prospective study of microvascular disease in the veteran population with heterogenous etiologies: chronic and acute CVD related to systemic vascular risk, TBI, and auto-immune/inflammatory disorders. She will propose a Merit Review application submitted before the end of the CDA period. Dr. Elahi is enthusiastically committed to improving the cognitive and mental health of Veterans through research, and with her proposed project and training, she will develop a thriving research program in VCID at the VA.