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Targeting RBC dysfunction in VCID

针对 VCID 中的红细胞功能障碍

基本信息

批准号：
10274266
负责人：
DAVID C. HESS
金额：
$ 156.54万
依托单位：
AUGUSTA UNIVERSITY
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：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10274266
关键词：
5&apos -AMP-activated protein kinase Affect Age Area Attention Bilateral Biological Markers Blood Blood - brain barrier anatomy Blood Cells Blood Pressure Blood flow Brain Brain Hypoxia Caliber Carotid Stenosis Cell physiology Cerebral small vessel disease Cerebrovascular Circulation Chronic Cognition Cognitive Coupled Data Dementia Dose Endocrine Endothelial Cells Enzymes Erythrocytes Erythroid Event Exercise Female Functional disorder Goals Human Hypoxia Impaired cognition Impairment Inflammation Intracranial Medullary Artery Lesion Limb structure Location Magnetic Resonance Imaging Matrix Metalloproteinases Measures Mediating Mediator of activation protein Microvascular Dysfunction Modeling Molecular Morphology Mus Mutant Strains Mice NOS3 gene Nitric Oxide Nitric Oxide Synthase Observational Study Outcome Oxygen Patients Perfusion Physical Exercise Play Procedures Production Property Research Role Signal Transduction Spin Labels Therapeutic White Matter Disease White Matter Hyperintensity age related aged arm endothelial dysfunction functional outcomes gray matter human subject hypoperfusion improved indexing ischemic conditioning male mimetics neurovascular coupling novel preservation prevent sensor shear stress white matter white matter damage

项目摘要

Red blood cell (RBC) dysfunction may play a major role in VCID. The RBC expresses NOS3 (eryNOS3), a key mediator of cerebral blood flow (CBF). Our long-term goal is to target RBC dysfunction (rheoerythrocrine) in patients with cerebral small vessel disease (SVD) and white matter (WM) damage, an unexplored area in dementia and VCID research. We advance the provocative hypothesis that age-related RBC dysfunction with reduced eryNOS3 and eryNO coupled with underlying endothelial dysfunction leads to reduced CBF, WM damage and cognitive impairment. A secondary hypothesis is that this RBC dysfunction can be targeted and ameliorated with physical exercise and chronic remote ischemic conditioning (C-RIC), an exercise mimetic. Our Specific Aims are: Aim 1. (Mice) Determine the contribution of the dose of eryNOS3 to WM damage, CBF, and cognitive outcomes in the bilateral carotid artery stenosis (BCAS) model. We will utilize male, female, and aged mutant mice lacking NOS3 in the erythroid lineage (eryNOS3-/- ) Aim 2. (Mice-Therapeutic) Determine if modulating and improving RBC dysfunction with C-RIC and/or physical exercise will improve cognition, reduce WM damage and improved functional outcomes. Aim 3. ( Human) Determine if C-RIC targets and improves RBC rheoerythrocrine biomarkers in human subjects with VCID and WM disease. .

红细胞（RBC）功能障碍可能在VCID中起主要作用。红细胞表达NOS 3（eryNOS 3），这是一个关键因素。脑血流介质（CBF）。我们的长期目标是针对红细胞功能障碍（rheoerythrocrine），患有脑小血管病（SVD）和白色物质（WM）损伤的患者，痴呆症和VCID研究。我们提出了一个挑衅性的假设，即与年龄相关的红细胞功能障碍与潜在的内皮功能障碍相结合的减少的eryNOS 3和eryNO导致减少的脑血流、脑白质损害与认知功能损害。一个次要的假设是，这种红细胞功能障碍可能是通过体育锻炼和慢性远程缺血调节（C-RIC），模仿的我们的具体目标是：目标1.（小鼠）确定eryNOS 3剂量对WM损伤、CBF和认知结果的贡献双侧颈动脉狭窄（BCAS）模型。我们将利用雄性、雌性和老年突变小鼠，红系细胞中的NOS 3（eryNOS 3-/-）目标2.（小鼠-治疗）确定是否用C-RIC和/或物理调节和改善RBC功能障碍运动可以改善认知，减少WM损伤，改善功能结果。目标3.（人类）确定C-RIC是否靶向并改善人类受试者的RBC流变性红细胞分泌生物标志物 VCID和WM疾病。 .