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.

抽象的年龄是心脑血管疾病和痴呆症最重要的危险因素。流行病学、临床前和临床数据表明，血管疾病与痴呆密切相关疾病，包括阿尔茨海默病 (AD) 和 AD 相关疾病，如血管性痴呆 (VaD)。这血管疾病、衰老和痴呆之间的机制联系仍然知之甚少。有越来越多的证据表明，medin 是一种由 50 个氨基酸组成的肽，是最常见但研究最少的肽之一人类淀粉样变性是血管老化病理的重要驱动因素。 Medin 在脉管系统中积聚与衰老有关，并与 AD、VaD 和主动脉疾病有关。人们对医学的机制知之甚少诱导细胞和组织损伤，目前尚不存在医学病理学的动物模型。我们展示了麦丁部分通过受体损害内皮功能和细胞活力并诱导促炎激活用于晚期糖基化终末产物 (RAGE)。我们的目标是发现医学的生物学途径使用新型全基因组 CRISPR/Cas9 敲除遗传筛选、测试 F(BA)S 肽和 RAGE 敲除可逆转 medin 毒性并测试 medin 在血管神经病理学中的体内作用通过创建内皮过度表达 medin 的小鼠模型。在目标 1 中，我们将探究有毒信号传导在内皮细胞中使用基于合成致死性的全基因组 CRISPR/Cas9 筛选机制。这将生成促进或防止药物毒性的候选基因/途径列表，并且可以成为潜在的药物靶点。在目标 2 中，我们将测试肽 F(BA)S 是否可以逆转培养物中的 Medin 毒性内皮细胞和离体分离的人类供体人脑动脉。在目标 3 中，我们将在体内测试 Medin 在衰老引起的血管和认知功能障碍中的作用，并评估 RAGE 敲除是否会保护的。在探索性子目标中，我们将创建内皮特异性地中海贫血的转基因小鼠模型过度表达。一旦成功实施，该提案将阐明机制血管神经病理学的基础医学，并创建了一种有价值的、新颖的临床前动物模型血管老化可用于识别和测试新药物靶点。