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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目总结/文摘