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Understanding vascular aging-related dementia through medin signaling

通过 medin 信号传导了解血管老化相关痴呆

基本信息

批准号：
10901026
负责人：
Ming Li
金额：
$ 47.16万
依托单位：
ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901026
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amino Acids Amyloidosis Animal Model Aortic Aneurysm Aortic Diseases Automobile Driving Autopsy Biological Blood Vessels Brain Pathology Candidate Disease Gene Cardiovascular Diseases Cell Survival Cerebrovascular Disorders Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Data Dementia Disease Drug Targeting EGF gene Endothelial Cells Endothelium Epidemiology Exposure to Functional disorder Gene Proteins Genes Genetic Screening Goals Human Impaired cognition Impairment In Vitro Inflammatory Injury Knock-out Knowledge Link Mediating Molecular Mus Mutation Outcome Study Pathologic Pathology Pathway interactions Peptides Phenotype Pre-Clinical Model Proteins Recombinants Risk Factors Role Signal Transduction Stress Testing Toxic effect Transgenic Mice Validation Vascular Dementia Vascular Diseases Wild Type Mouse aged brain endothelial cell cell injury cerebral artery cerebrovascular cognitive function cytotoxicity endothelial dysfunction genome-wide human disease in vivo in vivo evaluation insight knockout gene medin milk fat globule mouse model multidisciplinary neuroinflammation neuropathology neurovascular new therapeutic target next generation sequencing novel overexpression pre-clinical preservation prevent receptor for advanced glycation endproducts screening tissue injury

项目摘要

Abstract Age is the most important risk factor for cardio-cerebrovascular diseases and dementia disorders. Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia disorders, including Alzheimer's disease (AD) and AD-related disorders such as vascular dementia (VaD). The mechanistic links among vascular disease, aging and dementia remain poorly understood. There is growing evidence that medin, a 50-amino acid peptide that forms one of the most common yet least studied human amyloidoses, is an important driver of vascular aging pathologies. Medin accumulates in the vasculature with aging and is implicated in AD, VaD and aortic disease. Little is known as to the mechanisms by which medin induces cell and tissue injury, and no animal model of medin pathology currently exists. We showed that medin impaired endothelial function and cell viability and induced pro-inflammatory activation, in part through receptor for advanced glycation endproducts (RAGE). Our goals are to discover biological pathways of medin toxicity using novel genome-wide CRISPR/Cas9 knockout genetic screening, test F(BA)S peptide and RAGE knockout to reverse medin toxicity and test the in vivo role of medin in vasculo-neuropathology by creating a mouse model with endothelial overexpression of medin. In Aim 1, we will probe toxic signaling mechanisms using a synthetic lethality-based genome-wide CRISPR/Cas9 screening in endothelial cells. This will generate a list of candidate genes/pathways that facilitate or protect against medin toxicity and could be potential drug targets. In Aim 2, we will test if peptide F(BA)S can reverse medin toxicity in cultured endothelial cells and ex vivo in isolated human donor human cerebral arteries. In Aim 3, we will test in vivo the role of medin in aging-induced vascular and cognitive dysfunction and assess whether RAGE knockout will be protective. In an exploratory subaim, we will create a transgenic mouse model of endothelium-specific medin overexpression. Once successfully implemented, the proposal will shed light on the mechanisms underlying medin vasculo-neuropathology and create a valuable and novel preclinical animal model of vascular aging that can be used to identify and test new drug targets.

摘要