A Precision Medicine Approach To Study Targetable Pathways in Vascular Dementia

研究血管性痴呆靶向途径的精准医学方法

• 批准号: 10657534
• 负责人: Fanny M Elahi
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657534
• 关键词: Acute; Affect; Aging; Alzheimer' s Disease; Area; Artificial Intelligence; Astrocytes; Autoimmune; Autoimmune Diseases; Behavior; Big Data; Biological; Biological Markers; Blood; Blood Vessels; Brain; Brain imaging; Cells; Chronic; Clinic; Clinical; Clinical Data; Cognition; Cognitive; Collaborations; Data; Data Analytics; Data Collection; Data Science; Degenerative Disorder; Dementia; Development; Diagnostic; Disease; Disease Progression; Dissection; Early Diagnosis; Emotional; Endothelium; Enrollment; Ensure; Epidemic; Epidemiology; Etiology; Face; Failure; Fibrosis; Functional disorder; Funding; General Population; Goals; Homeostasis; Human Characteristics; Image; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Leadership; Machine Learning; Mediating; Mediation; Medicine; Mental Health; Mentors; Mentorship; Metabolic Diseases; Methods; Microvascular Dysfunction; Military Personnel; Modality; Modeling; Molecular; Molecular Biology; National Institute of Neurological Disorders and Stroke; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurology; Neurons; Neurosciences; Outcome; Pathogenicity; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Pattern; Perfusion; Phase; Phenotype; Physicians; Play; Prospective Studies; Proteomics; Research; Research Personnel; Risk; Role; Scientific Advances and Accomplishments; Scientist; Services; Site; Stroke; Synapses; System; Technical Expertise; Techniques; Technology; Testing; Therapeutic; Time; Toxicant exposure; Training; Traumatic Brain Injury; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Veterans; Vulnerable Populations; Work; accurate diagnostics; aging population; angiogenesis; biomarker development; biomarker discovery; biomarker identification; biomedical informatics; career; cerebrovascular biology; clinical biomarkers; clinical phenotype; clinical training; cognitive testing; cohort; dementia risk; diagnostic biomarker; disorder subtype; drug development; endophenotype; exosome; experience; human disease; hypoperfusion; improved; medical specialties; military veteran; molecular marker; multidimensional data; multimodal data; nervous system disorder; neuroimaging; neuroinflammation; neurovascular; novel; novel strategies; novel therapeutics; phenotypic biomarker; post-traumatic stress; precision medicine; predictive signature; programs; prospective; proteostasis; radiological imaging; resilience; retinal imaging; skills; success; tau Proteins; tau-1; therapeutic development; tool; unsupervised learning; vascular cognitive impairment and dementia

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.

Elahi 博士是一位早期职业医师兼科学家，接受过神经退行性疾病和 她在生物标志物开发方面拥有丰富的经验，希望在 VA 发展自己的职业生涯。通过结合她的临床 和分子生物学培训，Elahi 博士的长期目标是促进更好地了解 神经退行性疾病的血管通路，以改善早期诊断和 疾病缓解疗法的开发将改变许多人的认知轨迹 患有血管疾病和有痴呆风险的个体。为了实现这一目标，Elahi 博士 寻求额外的培训来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 VA 和 UCSF 开设专门诊所来评估因各种原因患有 VCID 的退伍军人， 高全身性血管疾病/风险、中风、TBI、自身免疫性疾病和神经退行性疾病以及 进行研究，（2）提高她在多模式数据驱动方面的科学技能 公正的生物标志物发现的分析方法。 为了更好地理解 VCID，我们需要能够处理人类疾病的复杂性的新工具 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 需要。作为一名医学科学家，Elahi 博士非常适合追求尖端方法 VCID 诊断技术的进步。然而，由于临床训练和责任，她还没有 获得有关公正的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。 在本申请中，Elahi 博士建议利用她在神经退行性疾病方面的临床专业知识和 外泌体技术方面的技术专长，以进行假设驱动的贡献建模 内皮炎症和致病性血管生成对不良临床和放射学脑结果的影响 VCID（目标 1 和 2）。在“目标 3”中，她与退伍军人事务部导师弗格森博士合作，首次 time 承担多维数据分析，包括外泌体蛋白质组学、脑成像、视网膜 影像学、临床变量和认知评分。拟议的工作范围与 Elahi 博士的工作范围一致 目标是成为转化 VCID 研究的领导者。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补充方法。这个目标将 提供进行离散临床生物标志物内表型的数据驱动发现的机会 在异质的受试者队列中。 这项研究预计将增进对 VCID 诊断和治疗相关性的理解 并为 Elahi 博士在 VCID 研究中的精准医学方法方面发挥领导作用做好准备。为确保成功 为了实现这项工作的科学和培训目标，Elahi 博士组建了一支世界一流的血管领域领导团队 神经病学和神经科学（Swanson）、神经退行性疾病（Miller）、神经病学数据科学 疾病（弗格森），以及顾问/合作者：弱势群体的流行病学和因果关系 推理 (Glymour)、多模态神经影像 (Rosen) 和 VCID 认知 (Kramer)。 Elahi 博士的培训 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。拟议的研究将为 Elahi 博士提供数据，用于更大规模的前瞻性研究 具有异质病因的退伍军人群体中的微血管疾病：慢性和急性CVD相关 全身性血管风险、TBI 和自身免疫/炎症性疾病。她将提出一项优点审查 CDA 期结束前提交的申请。 Elahi 博士热心致力于改善 通过研究以及她提出的项目和培训，她将提高退伍军人的认知和心理健康水平 在 VA 的 VCID 中开发一个蓬勃发展的研究项目。