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 本项目旨在了解整合素CD49a如何参与与年龄相关的脑膜丢失。 淋巴功能与认知功能减退和神经退行性疾病的发展，特别是 阿尔茨海默氏症。我们之前的研究表明，衰老与形态和 衰老小鼠脑膜淋巴功能的丧失和恢复 改善阿尔茨海默病小鼠模型的认知衰退和有限的生理病理。转录体 对老化淋巴管内皮细胞的分析表明，与细胞外基质和 微环境可能是其年龄相关性功能丧失的主要因素。然而，分子 控制与年龄相关的脑膜淋巴变性的机制仍不清楚。 我们的初步数据表明，整合素CD49a由淋巴管内皮细胞和 随着年龄的增长而增加。我们产生了一只小鼠，其中CD49a从淋巴管内皮细胞(LEC)中删除(使用 Prox1creERT2小鼠)，并发现LEC丢失CD49a可以改善它们的功能。此外，全基因组 相关研究已经确认CD49a是与阿尔茨海默病相关的基因。我们发现全球范围内 CD49a缺陷小鼠与阿尔茨海默病小鼠模型杂交后，淀粉样变性病理改变减轻 疾病。因此，我们假设这种与年龄相关的CD49a表达增加参与了他们的年龄- 相关的功能衰退，参与认知衰退的发展，并促进积累 阿尔茨海默病患者的淀粉样蛋白聚集物。 在我们初步数据的指导下，我们建议通过以下目标来解决我们的假设： 目的1：探讨CD49a在衰老过程中对脑膜淋巴功能的影响。 目的2：探讨CD49a在增龄性脑功能障碍中的作用。 总的来说，我们提出的研究将通过以下方式产生重大影响：a)揭示分子途径 调节与年龄相关的脑膜淋巴功能，b)强调脑膜淋巴的重要性 在衰老期间维持大脑健康的作用，以及c)提供证据证明 CD49a在衰老和神经退行性变中调节脑膜淋巴功能的作用