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.

项目摘要 本建议书的总体目标是支持候选人的职业发展和过渡到 独立研究员。概述的培训计划将使申请人具备必要的技能， 在丰富的，跨学科的和协作的环境中进行创新研究，促进 探索临床研究和试验的新途径。通过利用多模态成像技术， 分子和细胞蛋白质组学方法，候选人将加强已经很强的背景， 神经影像学，学习和整合新的方法，以获得更全面的了解阿尔茨海默病 疾病（AD）的病因学和病理生理学，并有助于成功的潜在的新疗法的AD。β-的 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，是最具靶向性的因子 进行治疗干预。然而，其他成分，如血管和炎症/免疫变化， 也发生在AD进展期间，增加了完全表征AD发病机制的复杂性。的 神经血管单位（NVU）与AD中血管、免疫和Aβ变化的研究相关，因为它包括 神经元-星形胶质细胞信号传导和血脑屏障，在Aβ清除中发挥作用。年龄相关 迟发性AD（LOAD）的合并症很难与AD相关变化区分开来， 疾病的进展。这项提案旨在将年龄与疾病相关的血管变化分离开来， 和免疫成分，并了解这些疾病相关变化对抗A β治疗的影响 结果。这将通过研究常染色体显性AD（ADAD）中的这些因素来实现，ADAD是一种罕见的形式 具有已知遗传病因和早期症状发作的AD。以前的研究利用蛋白质组学 评估NVU中断的方法和成像集中在LOAD群体上。目标1的目标 这项建议是评估已知ADAD相关突变携带者的NVU变化， 并生成NVU变化的蛋白质组学图谱。目标2的目标是定义 NVU破坏相对于其他已建立的疾病进展标志物的暂时性和关联性。 目标3的目的是确定NVU中断对Aβ清除治疗结局的影响，以及 治疗副作用的发生率以及与主要临床和认知结果的相关性。 成功完成这一拟议的研究项目将提高我们对血管的理解， AD中涉及的免疫相关过程及其与Aβ的关系，AD的病理生理学， 对给药相关Aβ变化的影响。