权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The roles of pericyte-derived laminin in neurovascular function and neurodegeneration

周细胞源性层粘连蛋白在神经血管功能和神经变性中的作用

基本信息

批准号：
10296497
负责人：
Yao Yao
金额：
$ 181.11万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10296497
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Astrocytes Basement membrane Biochemical Biological Assay Biological Process Blood - brain barrier anatomy Blood Vessels Brain Cells Cerebrovascular Circulation Defect Deposition Deterioration Development Disease Endothelial Cells Extracellular Matrix Functional disorder Generations Image Impaired cognition Impairment In Vitro Knockout Mice Label Laboratories Laminin Lead Maintenance Mediating Mission Molecular Molecular Target Molecular Weight Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Pathogenesis Perfusion Pericytes Protein Isoforms Proteins Quantitative Autoradiography Research Role Smooth Muscle Myocytes Structure Testing Therapeutic Thick Vascular Smooth Muscle age group age related blood-brain barrier disruption cognitive disability conditional knockout effective therapy fluorescein isothiocyanate dextran in vivo innovation laminin S macromolecule mouse model neuron loss neuronal survival neurovascular neurovascular unit novel receptor two photon microscopy two-photon

项目摘要

Project Summary/Abstract The long-term objective of this application is to understand whether the basement membrane (BM), the non-cellular component of the neurovascular unit, is involved in the pathogenesis of Alzheimer’s disease and can be targeted to treat Alzheimer’s disease and Alzheimer’s disease-related dementias. This is consistent with the mission of NIA. This proposal aims to investigate the biological functions of pericytic laminin in: (1) neurovascular function, including blood brain barrier (BBB) integrity, cerebral blood flow (CBF) and brain influx/efflux function, and (2) neuronal survival/function. In Aim 1, the function of pericytic laminin in BBB integrity will be investigated. First, whether and to what extent loss of pericytic laminin affects BBB integrity will be investigated using FITC-Dextrans of various molecular weights (Aim 1A). Next, the molecular mechanism underlying loss of pericytic laminin-induced BBB breakdown will be investigated, with a focus on changes in paracellular and transcellular transport in endothelial cells (Aim 1B). Furthermore, the receptors that mediate pericytic laminin’s effect in endothelial cells will be identified and examined (Aim 1C). In Aim 2, the function of pericytic laminin in CBF will be investigated. First, how loss of pericytic laminin affects CBF will be investigated using quantitative autoradiography and two-photon imaging (Aim 2A). Next, whether the reduced CBF is caused by pericyte loss/degeneration will be investigated in vitro and in vivo (Aim 2B). Furthermore, the receptors that mediate pericytic laminin’s effect in pericytes will be identified and examined (Aim 2C). In Aim 3, the role of pericytic laminin in brain influx/efflux function will be investigated. First, whether and how loss of pericytic laminin affects brain influx/efflux function will be investigated by influx/efflux assays using various fluorescently labeled macromolecules (Aim 3A). Next, whether the impaired influx/efflux function is due to BM damage and how loss of pericytic laminin affects BM composition/structure will be explored (Aim 3B). In Aim 4, the function of pericytic laminin in neuronal injury/neurodegeneration will be investigated. In this aim, whether loss of pericytic laminin leads to neuronal injury/neurodegeneration will be investigated at biochemical, structural, and functional levels. In addition, the age at which neuronal injury/neurodegeneration occurs will be determined and compared to that at which neurovascular dysfunction occurs. Successful completion of this study will elucidate the fundamental roles of pericytic laminin in neurovascular function and neuronal survival/function, and identify novel molecular targets with therapeutic potential in Alzheimer’s disease and Alzheimer’s disease-related dementias. In addition, this proposal may also lead to the generation of an innovative mouse model for neurodegeneration and open doors for new research.