Targeting RBC dysfunction in VCID

红细胞(RBC)功能障碍可能在VCID中起重要作用。RBC表达NOS3(EryNOS3)，一种键 脑血流介体(CBF)。我们的长期目标是针对RBC功能障碍(风湿性红细胞分泌) 脑部小血管疾病(SVD)和脑白质(WM)损害的患者，一个未知的区域 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 随着ERNOS3和ERNO的减少，再加上潜在的内皮功能障碍，导致减少 CBF、WM损害和认知损害。第二个假设是，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适应(C-RIC)这一运动来靶向和改善 模仿者。我们的具体目标是： 目的1.(小鼠)确定药物剂量对WM损伤、脑血流量和认知结果的影响 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缺乏 红系中的NOS3(eryNOS3-/-) 目的2.(小鼠治疗)确定是否通过C-RIC和/或物理手段调节和改善RBC功能障碍 运动将改善认知，减少WM损伤，并改善功能结果。 患有VCID和西医病。 。

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. .