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Translational analysis of cerebrovascular dysfunction in aging

衰老过程中脑血管功能障碍的转化分析

基本信息

批准号：
10077916
负责人：
Andriy Yabluchanskiy
金额：
$ 29.56万
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：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077916
关键词：
Affect Age Age-Years Aging Animal Model Animals Aorta Astrocytes Biological Availability Brain Cell Aging Cell physiology Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Clinical Clinical Research Cognition Cognitive DNA Damage Data Elderly Endothelial Cells Endothelium Excision Functional Magnetic Resonance Imaging Functional disorder Gait Gait abnormality Genetic Geroscience Health Care Costs Hormones Human Impaired cognition Impairment Individual Insulin-Like Growth Factor I Insulin-Like Growth-Factor Binding Protein 1 Insulin-Like-Growth Factor I Receptor Intervention Laser Speckle Imaging Lead Mediating Modeling Molecular Motor Mus Near-Infrared Spectroscopy Neurons Nitric Oxide Oxidative Stress Pathology Performance Peripheral Personal Communication Pharmacology Phenotype Plasma Play Process Quality of life Reporter Research Research Design Role Signal Transduction Stimulus Stress Testing Time Tissues Vascular Cognitive Impairment age group age related aged aging brain base cell type cerebral hemodynamics cognitive function cognitive performance disability endothelial dysfunction functional disability human subject improved improved outcome in vivo knock-down middle age mouse model neurovascular coupling neurovascular unit novel novel strategies prevent response restoration senescence transcriptomics translational study

项目摘要

ABSTRACT Age-related vascular cognitive impairment (VCI) and gait abnormalities are the two most common causes of disability in older adults that lead to loss of independence and severely reduce quality of life. Recent studies have concluded that cerebromicrovascular pathologies play an important role in the manifestation of VCI and gait abnormalities. One of the fundamental roles of the cerebrovasculature is to match cerebral blood flow (CBF) with energetic demands of neurons through a process known as neurovascular coupling (NVC). NVC maintains an optimal cerebral tissue microenvironment and requires microvascular dilation induced by nitric oxide (NO) released from cerebromicrovascular endothelial cells (CMVECs) in response to neuronal/astrocytic activation. Recent studies demonstrate that inhibition of NO-mediated NVC responses in mice results in impaired cognitive performance and gait abnormalities. Importantly, one of the factors that regulates NVC and cognition in animal models is the vasoprotective hormone insulin-like growth factor-1 (IGF-1) that has been shown to decrease with age and influences many cell-types in brain. Recent findings suggest that age-related decline of circulating IGF- 1 promotes stress and DNA damage and is associated with increased expression of markers of cellular senescence in brain and aorta. Despite recent advances, there is a critical gap in our understanding related to specific molecular mechanisms that promote cerebromicrovascular endothelial dysfunction in aging, and whether the age-dependent deficiency of circulating IGF-1 is associated with impairments in NVC and higher brain functions (including cognition and gait) in humans. Our overall hypothesis is that age-associated IGF-1 deficiency promotes endothelial dysfunction and impairments in NVC by inducing endothelial cell senescence, which contribute to cognitive impairment and gait abnormalities in older animals and humans. The following aims are proposed: Aim 1) Assess whether dysfunction of NVC is mediated through a specific effect of IGF-1 deficiency on CMVECs and whether endothelial cell senescence contributes to this impairment. In this aim we will use novel model ofdisruption of IGF-1 signaling specifically in endothelial cells and a novel mouse model (p16-3MR) which allows to specifically eliminate senescent cells. Aim 2) Determine the relationship between age, circulating IGF-1 status, endothelial function, NVC responses, cognition and gait in human subjects.

摘要