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。 RBC表示NOS3（ERYNOS3），钥匙脑血流（CBF）的介体。我们的长期目标是针对RBC功能障碍（RheoeryThrocrine）患有脑小血管疾病（SVD）和白质（WM）损害的患者，在未探索的地区痴呆和VCID研究。我们推进了与年龄相关的RBC功能障碍的挑衅性假设递减的ERYNOS3和ERYNO与潜在的内皮功能障碍相结合会导致减少 CBF，WM损害和认知障碍。次要假设是这种RBC功能障碍可以是通过体育锻炼和慢性远程缺血条件（C-RIC）进行靶向和改善，锻炼模仿。我们的具体目的是：目标1。（小鼠）确定erynos3剂量对WM损伤，CBF和认知结果的贡献在双侧颈动脉狭窄（BCAS）模型中。我们将利用缺乏男性，女性和老年突变小鼠红细胞谱系中的NOS3（Erynos3 - / - ）目标2。（小鼠 - 治疗性）确定是否使用C-RIC和/或物理来调节RBC功能障碍并改善RBC功能障碍运动将改善认知，减少WM损害并改善功能结果。目标3。（人）确定C-RIC目标是否改善了人类受试者中的RBC RheoeryThrictracrine生物标志物患有VCID和WM疾病。。