Targeting Neurovascular Dysfunction in AD

针对 AD 中的神经血管功能障碍

基本信息

批准号：
9056264
负责人：
NARAYAN R BHAT
金额：
$ 22.43万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056264
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid deposition Apolipoprotein A-I Astrocytes Atherosclerosis Basement membrane Behavioral Biochemical Biological Preservation Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Cerebrovascular Circulation Cerebrovascular system Clinical Cognitive Collagen Type IV Dementia Diabetes Mellitus Disease Dose DsRed Dystrophin Energy Supply Environment Extravasation Functional disorder Future Goals Health High Fat Diet Hyperemia Hyperglycemia Image Imaging Techniques Immunotherapy Impaired cognition Inflammation Injection of therapeutic agent Injury Insulin Resistance Lead Leukocyte Rolling Link Mediating Membrane Proteins Metabolic Metabolic Diseases Microscopy Modeling Monitor Mus Neurodegenerative Disorders Neurons Non-Insulin-Dependent Diabetes Mellitus Outcome Outcome Study Oxidative Stress Pathogenesis Pathology Peptides Pericytes Play Property Proteins Reporter Research Resistance Role Signal Transduction Smooth Muscle Myocytes Streptozocin Stroke Synapses Techniques Testing Therapeutic Toxin Treatment Efficacy Vascular Cognitive Impairment Vascular Diseases Vasodilation Western Blotting aquaporin 4 base capillary cell injury cerebrovascular diabetic efficacy testing foot hypoperfusion improved in vivo in vivo imaging innovation insulin signaling member mouse model neurotoxic neurovascular neurovascular coupling neurovascular unit non-genetic novel novel therapeutics peptidomimetics public health relevance response targeted therapy trials two-photon vascular contributions vascular inflammation venule

项目摘要

DESCRIPTION (provided by applicant): In the wake of failed amyloid-targeted drug trials and immune therapies, recent efforts are directed towards a broad range of alternative mechanisms of Alzheimer's disease (AD) including, in particular vascular dysfunction. The overall goal of our research is to define cerebrovascular dysfunction as a mechanistic link between cardiometabolic disorders such as type 2-diabetes (T2DM) and AD and as a potential target for vasculoprotective strategies in AD treatment. The present project utilizes a mouse model of AD with non-genetically induced T2DM that shows accelerated amyloid deposition with cognitive impairment. The approach uses innovative techniques and strategies including the use of 2-photon imaging focused on vascular changes (i.e., pericyte loss/injury, astrocyte endfeet and blood brain barrier disruption correlated with increased vascular amyloid) and responses i.e., altered functional hyperemia (cerebral blood flow) and vasodilation potentially leading to metabolic/synaptic dysfunction and cognitive decline. In a therapeutic approach, we will test the efficacy of a novel Apo AI mimetic peptide (5A) with demonstrated vasculoprotective properties, in the diabetic AD model. The outcome of these studies should provide strong and direct support to the vascular hypothesis of AD and further suggest new therapeutics to limit vascular triggers of AD pathogenesis.

描述（由适用提供）：在失败的淀粉样蛋白靶向药物试验和免疫室之后，最近的努力针对阿尔茨海默氏病（AD）的广泛替代机制（包括血管功能障碍）。我们研究的总体目的是将脑血管功能障碍定义为心脏代谢性疾病（例如2型糖尿病型（T2DM）和AD）之间的机械联系，以及在AD治疗中的血管抑制策略的潜在目标。本项目利用具有非生成诱导的T2DM的AD小鼠模型，该模型显示出具有认知障碍的加速淀粉样蛋白沉积。该方法使用创新的技术和策略，包括使用的2光子成像，重点是血管变化（即周围的损失/受伤，星形胶质细胞末端和血液脑屏障与血管淀粉样蛋白增加相关）和反应，即响应，即改变功能性和脑血液流动性和依从性血液流动性，并具有综合性的综合剂量促进剂量促进剂量促进剂量促进剂量促成，分别为综合促成综合促成，促成了综合的促进剂量促成，促成了综合促进剂量促进剂量促成综合促进剂量促成。衰退。在治疗方法中，我们将在糖尿病AD模型中测试具有具有血管保护特性的新型Apo AI模拟肽（5A）的有效性。这些研究的结果应为AD的血管假设提供强烈而直接的支持，并进一步提出新的治疗剂，以限制AD发病机理的血管触发。