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

Age-related vascular cognitive impairment: role of endothelial senescence

年龄相关的血管认知障碍：内皮衰老的作用

基本信息

批准号：
10222565
负责人：
Anna Csiszar
金额：
$ 36.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10222565
关键词：
Abbreviations Affect Age-associated memory impairment Aging Attenuated Blood - brain barrier anatomy Blood capillaries Brain Cell Aging Cells Cellular Morphology Cellular biology Cerebrovascular Circulation Cerebrum Characteristics Chimeric Proteins Cognition Cognitive Consequentialism DNA Damage Data Endothelial Cells Endothelium Functional Magnetic Resonance Imaging Functional disorder Ganciclovir Gene Expression Heterogeneity Homeostasis Human Hyperemia Image Imaging Techniques Impaired cognition Impairment Intervention Laser Speckle Imaging Learning Maintenance Matrix Metalloproteinases Mediating Mediator of activation protein Memory Modality Morphology Mus Neuronal Dysfunction Neurons Nutrient Oxidative Stress Oxygen Pathogenesis Pathway interactions Phenotype Play Prevention Production Proteomics Publishing Radiation therapy Regulation Reporter Rodent Model Role Series Structure Testing Tight Junctions Vascular Cognitive Impairment Vascular blood supply Vasodilator Agents Work age related aged aging brain base blood-brain barrier disruption blood-brain barrier function brain endothelial cell cell type cellular imaging cerebrovascular cognitive performance cost estimate cytokine density endothelial dysfunction functional disability genetic manipulation human old age (65+)improved liposomal delivery microvascular aging mouse model network architecture neuroinflammation neurovascular neurovascular coupling neurovascular unit novel older patient paracrine prevent programs red fluorescent protein response senescence stressor transcriptomics two-photon vascular cognitive impairment and dementia

项目摘要

PROJECT SUMMARY/ ABSTRACT More than 50 million people over the age of 65 are currently affected by vascular cognitive impairment and dementia (VCID). Although the specific mechanisms for aging- induced VCID are not yet known, there is increasing evidence that alterations of the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of senescence-related endothelial dysfunction in cognitive impairment. The central hypothesis is that aging primarily promotes endothelial senescence in the brain and subsequent dysfunction, altering the production of vasodilator mediators, impairing neurovascular coupling responses, promoting blood-brain barrier (BBB) disruption and microvascular rarefaction. The resulting decline in cerebral blood flow (CBF) and increased neuroinflammation contribute to cognitive impairment. The proposed work is novel as it will be the first to demonstrate that aging-induced endothelial senescence is a critical contributing factor to the pathogenesis of VCID. The results will likely identify specific mechanisms and reveal potential therapies that are capable of improving CBF and restoring learning and memory. The following aims are proposed: 1) Determine how endothelial senescence alters neurovascular coupling responses, CBF and cognition in aging. The working hypothesis is that aging-induced activation of p16-dependent cellular senescence program in endothelial cells impairs vasodilator function. It is predicted that elimination of senescent endothelial cells, through genetic manipulation or through senolytic therapies will restore neurovascular function and improve CBF and cognition in aged mice. 2) Determine how senescence alters microvascular density and BBB integrity in aging. The working hypothesis is that activation of p16-dependent cellular senescence program in endothelial cells impairs endothelial barrier function and compromise the maintenance of the microcirculatory network. It is predicted that elimination of senescent cells will restore BBB, attenuating neuroinflammation and increase cerebromicrovascular density in aged mice. 3) Determine cellular heterogeneity among senescent endothelial cells in conjunction with their morphological and functional characteristics. Together, the proposed studies will identify a fundamental mechanism governing aging-induced cerebrovascular changes eventually leading to cognitive impairment.

项目摘要/摘要