Integrin mediated regulation of lymphatics during aging and neurodegeneration

衰老和神经变性过程中整合素介导的淋巴管调节

• 批准号: 10428808
• 负责人: Antoine Louveau
• 金额: $ 44.28万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428808
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloidosis; Behavior; Behavioral; Biological Assay; Brain; CD22 gene; Cerebrospinal Fluid; Cervical lymph node group; Cognitive; Collagen; Collagen Fiber; DLG4 gene; Data; Development; Disease; Drainage procedure; Dura Mater; Electron Microscopy; Ensure; Extracellular Matrix; Flow Cytometry; Functional disorder; Future; Generations; Genes; Glial Fibrillary Acidic Protein; Goals; Growth Factor; Hippocampus (Brain); Homeostasis; Immune; Immunohistochemistry; Impaired cognition; Integrin Binding; Integrins; Knowledge; Life; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Maintenance; Mediating; Meningeal; Meningeal lymphatic system; Meninges; Methods; Molecular; Morphology; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Ovalbumin; Parkinson Disease; Pathology; Pathway interactions; Patients; Prefrontal Cortex; Regenerative capacity; Regulation; Risk Factors; Role; Scheme; Signal Transduction; Synapses; Testing; Therapeutic; Tight Junctions; Tracer; Up-Regulation; age effect; aged; aging brain; brain dysfunction; brain health; cognitive development; conditional knockout; conditioned fear; functional decline; functional loss; genome-wide; immunoregulation; improved; improved functioning; in vivo imaging; loss of function; lymphatic dysfunction; lymphatic vasculature; middle age; mouse model; nervous system disorder; neurogenesis; new therapeutic target; normal aging; novel; object recognition; social; transcriptomics; young adult

PROJECT SUMMARY/ABSTRACT This project aims at understanding how the integrin CD49a participates in age-associated loss of meningeal lymphatic function and in the development of cognitive decline and neurodegenerative diseases, particularly Alzheimer's disease. Our previous studies demonstrated that aging correlated with both morphological and functional loss of meningeal lymphatic function, and that restoring meningeal lymphatic function in aging mice improved cognitive decline and limited physiopathology in a mouse model of Alzheimer's disease. Transcriptomic analysis of aged lymphatic endothelial cells revealed that interactions with the extracellular matrix and the microenvironment may represent major factors in their age-associated loss of function. However, the molecular mechanisms controlling the age-associated degeneration of the meningeal lymphatic remains unknown. Our preliminary data demonstrate that the integrin CD49a is expressed by lymphatic endothelial cells and increases with aging. We generated a mouse where CD49a is deleted from lymphatic endothelial cells (LEC) (using the Prox1creERT2 mice), and found that loss of CD49a by LEC improves their function. Furthermore, genome-wide associated studies have identified CD49a as an associated gene with Alzheimer's disease. We found that global CD49a-deficient mice have reduced amyloidosis pathology when crossed with a mouse model of Alzheimer's disease. We therefore hypothesize that this age-associated increase in CD49a expression participates in their age- associated functional decline, participates in the development of cognitive decline, and promotes the accumulation of amyloid aggregates in Alzheimer's disease. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim 1: Determine the effects of CD49a in meningeal lymphatic function during aging. Aim 2: Delineate how CD49a expression by LEC contributes to age-associated brain dysfunction. Collectively, our propose studies will have a significant impact by: a) revealing a molecular pathway regulating age-associated meningeal lymphatic function, b) highlighting the importance of meningeal lymphatic function in the maintenance of brain health during aging, and c) providing evidence for the therapeutic potential of CD49a to manipulate meningeal lymphatic function in aging and neurodegeneration.

项目摘要/摘要 该项目旨在了解整合素CD49A如何参与与年龄相关的脑膜损失 淋巴功能以及认知下降和神经退行性疾病的发展，特别是 阿尔茨海默氏病。我们以前的研究表明，衰老与形态学和 脑膜淋巴功能的功能丧失，以及衰老小鼠的脑膜淋巴功能 在阿尔茨海默氏病小鼠模型中，认知能力下降和生理病理学有限。转录组 对老年淋巴内皮细胞的分析表明，与细胞外基质的相互作用和 微环境可能代表其与年龄相关的功能丧失的主要因素。但是，分子 控制脑膜淋巴的年龄相关变性的机制仍然未知。 我们的初步数据表明，整联蛋白CD49A由淋巴内皮细胞和 随着衰老而增加。我们生成了一个从淋巴内皮细胞（LEC）中删除CD49A的小鼠（使用 Prox1creert2小鼠），发现LEC损失CD49A会改善其功能。此外，全基因组 相关研究已将CD49A确定为与阿尔茨海默氏病的相关基因。我们发现全球 当与阿尔茨海默氏症小鼠模型交叉时，CD49A缺乏小鼠降低了淀粉样病病理学 疾病。因此，我们假设CD49A表达与年龄相关的增加参与其年龄 - 相关的功能下降，参与认知下降的发展，并促进积累 阿尔茨海默氏病中的淀粉样蛋白聚集体。 在我们的初步数据的指导下，我们建议使用以下目的解决我们的假设： 目标1：确定CD49A在衰老过程中脑膜淋巴功能的影响。 AIM 2：描述LEC的CD49A表达如何有助于与年龄相关的脑功能障碍。 总的来说，我们的建议研究将产生重大影响：a）揭示分子途径 调节年龄相关的脑膜淋巴功能，b）突出显示脑膜淋巴的重要性 在衰老过程中维持大脑健康的功能，c）提供证据证明具有治疗潜力的证据 CD49A在衰老和神经变性中操纵脑膜淋巴功能。