Evaluation of the neurovascular unit in the setting of pathogenesis and treatment of autosomal dominant Alzheimer disease

常染色体显性阿尔茨海默病发病机制和治疗中神经血管单位的评估

• 批准号: 10572223
• 负责人: Nelly Cecile Joseph-Mathurin
• 金额: $ 9.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572223
• 关键词: Abeta clearance; Age; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Astrocytes; Atrophic; Biological; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Cardiovascular Diseases; Career Mobility; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cessation of life; Clinical; Clinical Research; Clinical Trials; Cognitive; Dementia; Disease; Disease Marker; Disease Progression; Edema; Endothelial Cells; Etiology; Evaluation; Excision; FDA approved; Functional disorder; Genes; Genetic Predisposition to Disease; Goals; Hemorrhage; Image; Imaging Techniques; Immune; Immunologic Factors; Impaired cognition; Incidence; Individual; Inflammatory; Inflammatory Response; Investigation; Knowledge; Late Onset Alzheimer Disease; Learning; Link; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Microvascular Dysfunction; Molecular; Molecular Target; Multimodal Imaging; Mutation; Neuroglia; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pericytes; Pharmaceutical Preparations; Phase; Play; Population; Positron-Emission Tomography; Process; Proteins; Proteomics; Reporting; Research; Research Personnel; Research Project Grants; Role; Safety; Serum; Signal Transduction; Symptoms; Techniques; Therapeutic; Therapeutic Intervention; Training; Treatment Side Effects; Treatment outcome; White Matter Hyperintensity; Work; abeta accumulation; age related; associated symptom; autosomal dominant Alzheimer' s disease; blood-brain barrier disruption; career development; clinical effect; clinical efficacy; collaborative environment; comorbidity; drug development; early onset; imaging biomarker; improved; individual response; innovation; insight; magnetic resonance imaging biomarker; neuroimaging; neurovascular unit; next generation; novel; novel strategies; novel therapeutics; pharmacologic; pre-clinical; protein metabolism; proteomic signature; response; skills; success; targeted treatment; treatment response; vascular contributions; vascular factor; β-amyloid burden

PROJECT SUMMARY The overall objective of this proposal is to support the candidate’s career development and transition to that of an independent researcher. The outlined training plan will equip the applicant with the necessary skills to conduct innovative research in a rich, interdisciplinary, and collaborative environment, facilitating the investigation of new avenues of clinical research and trials. By utilizing multimodal imaging techniques and molecular and cellular proteomic approaches, the candidate will reinforce an already strong background in neuroimaging, learn and integrate new approaches to gain a greater holistic understanding of Alzheimer disease (AD) etiology and pathophysiology, and contribute to the success of potential new therapies for AD. β- amyloid (Aβ), one of the earliest biomarkers to accumulate during AD progression, is the most targeted factor for therapeutic intervention. However, other components, such as vascular and inflammatory/immune changes, also occur during AD progression, adding to the complexity of fully characterizing AD pathogenesis. The neurovascular unit (NVU) is relevant to the study of vascular, immune, and Aβ changes in AD, as it comprises neuronal-astrocyte signaling and the blood-brain barrier, which play a role in Aβ clearance. Age-related comorbidities in late-onset AD (LOAD) are challenging to distinguish from AD-related changes involved in the progression of the disease. This proposal aims to disconnect age- from disease-related changes to vascular and immune components and to understand the impact of these disease-related changes on anti-Aβ treatment outcomes. This will be accomplished by studying these factors in autosomal dominant AD (ADAD), a rare form of AD with a known genetic etiology and with early age of symptom onset. Previous studies utilizing proteomic approaches and imaging to assess NVU disruption have focused on LOAD populations. The goal of Aim 1 of this proposal is to assess changes in the NVU in known carriers of ADAD-related mutations and with markers of vascular changes and generate a proteomic profile of NVU changes. The goal of Aim 2 is to define the temporality and association of NVU disruption relative to other established markers of disease progression. The goal of Aim 3 is to define the influence of NVU disruption on outcomes of Aβ clearance therapies, as well as on the incidence of treatment side effects and the association with primary clinical and cognitive outcomes. Successful completion of this proposed research project will improve our understanding of the vascular- and immune-related processes involved in AD and their relationship with Aβ, the pathophysiology of AD, and their influence on treatment-related Aβ changes.

项目概要 该提案的总体目标是支持候选人的职业发展和过渡到 概述的培训计划将为申请人提供必要的技能 在丰富的跨学科和协作环境中进行创新研究，促进 利用多模态成像技术探索临床研究和试验的新途径。 分子和细胞蛋白质组学方法，候选人将加强已经强大的背景 神经影像学，学习和整合新方法，以更全面地了解阿尔茨海默病 疾病（AD）的病因学和病理生理学，并有助于 AD 潜在新疗法的成功。 淀粉样蛋白 (Aβ) 是 AD 进展过程中最早积累的生物标志物之一，也是最具针对性的因子 然而，其他成分，例如血管和炎症/免疫变化， 也发生在 AD 进展过程中，这增加了充分表征 AD 发病机制的复杂性。 神经血管单元 (NVU) 与 AD 中血管、免疫和 Aβ 变化的研究相关，因为它包含 神经元星形胶质细胞信号传导和血脑屏障，在年龄相关的 Aβ 清除中发挥作用。 迟发性 AD (LOAD) 的合并症很难与 AD 相关的变化区分开来。 该提案旨在将年龄与疾病相关的血管变化分开 和免疫成分，并了解这些疾病相关变化对抗 Aβ 治疗的影响 这将通过研究常染色体显性 AD (ADAD)（一种罕见的形式）中的这些因素来实现。 具有已知遗传病因且症状发作较早的 AD 研究利用蛋白质组学。 评估 NVU 破坏的方法和成像主要针对 LOAD 人群。目标 1 的目标。 该提案旨在评估已知 ADAD 相关突变携带者和标记物的 NVU 变化 目标 2 的目标是定义血管变化并生成 NVU 变化的蛋白质组学谱。 NVU 相对破坏的时间性和与其他已确定的疾病进展标志物的关联。 目标 3 的目标是确定 NVU 破坏对 Aβ 清除疗法结果的影响，以及 治疗副作用的发生率以及与主要临床和认知结果的关联。 成功完成这个拟议的研究项目将提高我们对血管和 AD 涉及的免疫相关过程及其与 Aβ 的关系、AD 的病理生理学及其 对治疗相关的 Aβ 变化的影响。