Cerebral vascular calcium signaling in diabetic Alzheimer's disease-related dementias

糖尿病阿尔茨海默病相关痴呆的脑血管钙信号传导

基本信息

批准号：
10117843
负责人：
YONG-XIAO WANG
金额：
$ 32.6万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117843
关键词：
Address Agreement Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animals Award Biology Blood Blood Vessels Blood flow Calcium Signaling Cell Hypoxia Cells Cerebrovascular Circulation Cerebrum Cessation of life Cognitive Complex Data Dementia Deterioration Development Diabetes Mellitus Diabetic mouse Disease Dissociation Funding Funding Opportunities Hypoxia Impaired cognition In Vitro Knock-out Lead Link Mediating Mediation Memory Memory Loss Memory impairment Mitochondria Molecular Mus Nerve Degeneration Organ Oxidative Stress Pathologic Pathway interactions Pilot Projects Process Production Reactive Oxygen Species Research Research Personnel Rieske iron-sulfur protein Risk Factors Role Ryanodine Receptor Calcium Release Channel Series Site Smooth Muscle Smooth Muscle Myocytes Tacrolimus Binding Proteins Testing United States National Institutes of Health Vascular Dementia Vascular Smooth Muscle Wild Type Mouse Work antioxidant therapy base cerebral artery cerebral hypoperfusion cerebrovascular comorbidity diabetic experimental study glucose metabolism improved in vivo innovation knockout gene new therapeutic target novel overexpression programs protein expression response therapeutic target therapeutically effective vascular cognitive impairment and dementia vasoconstriction

项目摘要

Alzheimer's disease (AD) and AD-related dementias (ADRD) are the common incurable neurodegenerative even conditions characterized by progressive cognitive deterioration, memory decline and death. The major forms of ADRD include vascular contributions to cognitive impairment and dementia (VCID). In agreement, vascular dementia is the second most common form of dementia and the most frequent comorbidity with AD. Diabetes may production is a leading factor in the development of VCID; the ole of diabetes primarily occur due to the abnormal glucose metabolism and i ncreased reactive oxygen species (ROS) in cerebral vascular smooth muscle cells (CASMCs) r . In support, antioxidant therapies have shown promising results in protecting against diabetes-induced VCID and other dementias. the molecular mechanisms that link diabetes to the development of VCID remain to be elucidated, and current treatments for these diseases are neither always effective nor specific. The Based on our preliminary findings with previous work, in this project, we propose a novel central hypothesis that diabetes increases Rieske iron-sulfur protein (RISP)-mediated mitochondrial ROS, dissociates FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) to remove its inhibitory effect on RyR2 channel and induce Ca2+ release, which causes cerebral vasoconstriction and cerebral blood flow reduction, thereby leading to progressive memory loss, cognitive decline and VCID. To test this exciting hypothesis, we will conduct a series of mechanistic studies primarily by employing smooth muscle-specific RISP, RyR2, and FKBP12.6 knockout (KO) and/or overexpression (OE) mice with other complementary advanced experimental approaches to address the following specific questions (Specific Aims): Aim 1: Are the increased RISP-mediated mitochondrial ROS in CASMCs essential for VCID induced by diabetes? Aim 2: Is RyR2/FKBP12.6 complex dissociation a key consequence for the increased RISP-mediated mitochondrial ROS to mediate VCID induced by diabetes? The objectives of the present proposal are not only to enhance our understanding of the molecular mechanisms for VCID, ADRD devastating diseases. and AD, but also help to identify novel therapeutic targets for these common

阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRD）是常见的无法治愈的神经退行性甚至以进行性认知恶化，记忆力下降和死亡。 ADRD的主要形式包括对认知障碍和痴呆的血管贡献（VCID）。一致，血管性痴呆是第二常见的痴呆形式，也是最常见的形式 AD的合并症频繁。糖尿病可能生产是VCID发展的主要因素；糖尿病的油主要是由于异常葡萄糖代谢而发生的，而活性氧（ROS）在脑血管平滑肌细胞（CASMC）中 r 。为了支持，抗氧化剂疗法具有显示出有望防止糖尿病诱导的VCID和其他痴呆症的结果。这将糖尿病与VCID发育联系起来的分子机制尚待阐明，并且这些疾病的当前治疗既不总是有效也不具体的。这根据我们先前工作的初步发现，在这个项目中，我们提出了一个新颖的中心假设糖尿病增加了瑞氏铁硫蛋白（RISP）介导的线粒体ROS，从2型ryanodine受体（RYR2）中分离FK506结合蛋白12.6（FKBP12.6）去除其对RYR2通道的抑制作用并诱导Ca2+释放，这会导致脑血管收缩和脑血流减少，从而导致记忆力丧失，认知能力下降和VCID。为了检验这一令人兴奋的假设，我们将主要通过采用一系列机械研究平滑肌特异性RISP，RYR2和FKBP12.6敲除（KO）和/或过表达（OE）小鼠带有其他互补的高级实验方法来解决以下特定问题（特定目的）： AIM 1：在CASMC中，RISP介导的线粒体ROS是否增加了VCID所诱导的VCID 糖尿病？ AIM 2：RYR2/FKBP12.6复合物解离是RISP介导的增加的关键结果线粒体ROS介导糖尿病诱导的VCID？本提案的目标不仅是为了增强我们对分子的理解 VCID的机制，ADRD 毁灭性疾病。和广告，但也有助于确定这些常见的新型治疗靶标