Targeting RBC dysfunction in VCID

红细胞（RBC）功能障碍可能在VCID中起主要作用。红细胞表达NOS3（eryNOS3），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eryNOS3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NOS3（eryNOS3-/-） 目标二。（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。 .

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. .