Administrative Supplement to Award "Circadian regulation of vascular aging"

摘要：衰老是多种疾病的主要危险因素，尤其是阿尔茨海默病(AD)和 心血管疾病。血管对认知损害和痴呆(VCID)的贡献排在第二位 AD后痴呆的常见原因。中脑区域的血管损伤导致进行性认知 与阿尔茨海默病相似的损害；血管性痴呆通常与阿尔茨海默氏斑共存。因此， 更好地了解VCID可能会提供新的解决方案，改善VCID的预防和管理，并 广告。脑血管功能障碍，以脑血管病变和脑梗塞为特征，限制血流，减少 向大脑提供氧气和营养物质，导致大脑活动和认知功能受损。 血管老化不仅损害正常的血管收缩和顺应性，而且还增加了 心血管疾病，包括高血压、中风和外周动脉疾病。临床、流行病学 实验研究表明，多种血管疾病，如中风、高血压、 动脉粥样硬化和动脉僵硬与VCID相关，并加速认知进展 损伤和痴呆症。我们目前由NHLBI资助的家长提案《血管昼夜节律调节器》 衰老“(5R01HL146103)旨在揭示以前未知的成骨大师的功能 转录因子Runx2在血管平滑肌细胞发育过程中的作用 血管老化的症状。母公司的建议侧重于研究大体动脉僵硬和钙化 并试图通过昼夜节律调节来定义先前未知的Runx2的调节 蛋白质O-GlcN酰化。Parent Proposal中的研究发现小鼠主动脉中Runx2表达增加 以与年龄相关的方式，这与脉搏波速度(PWV)的增加有关，这是一种 动脉僵硬是未来心血管事件的预测因子。初步研究确定，Runx2 SMC缺乏抑制了动脉僵硬，改善了脑血流量。此外，患有SMC的小鼠- 特定的Runx2删除在水迷宫测试中寻找目标所需的时间更短，在开阔的场地中移动速度更快 测试表明，认知功能得到了改善。这些令人兴奋的观察表明Runx2扮演了一个新的角色 在SMC中调节脑动脉血流和认知功能。因此，本附录应用程序将 利用SMC特有的两个新的BMAL1(时钟功能障碍)和OGT(O-GlcN酰化)缺失 消融)小鼠模型，以揭示BMAL1/OGT/Runx2的新功能 在调节脑血管功能和VCID方面，信号级联反应。此外，我们还将剖析不同的 和重叠的分子决定在两个血管系统，主动脉和脑，使用无偏系统 生物学方法，这可能导致识别新的信号级联和特征细胞群 独一无二地调节脑血管功能和血管紧张性肠病；并为 预防与年龄相关的血管疾病，改善公共健康和寿命。

Abstract: Aging is the major risk factor for a variety of diseases, particularly Alzheimer's dementia (AD) and cardiovascular diseases. Vascular contribution to cognitive impairment and dementia (VCID) is the second most common cause of dementia after AD. Vascular damage in the mid-brain regions causes progressive cognitive impairment similar to that of AD; and vascular dementia often coexists with Alzheimer's plaques. Therefore, better understanding of VCID may provide new solutions that improve prevention and management of VCID and AD. Cerebrovascular dysfunction, featuring brain vascular lesions and infarctions, limits blood flow and reduces oxygen and nutrient supply to the brain which results in impairment of brain activity and cognitive function. Vascular aging not only impairs normal vascular contraction and compliance but also increases the incidence of cardiovascular disease, including hypertension, stroke and peripheral artery disease. Clinical, epidemiological and experimental studies have demonstrated that multiple vascular diseases, such as stroke, hypertension, atherosclerosis and arterial stiffness, are associated with VCID and accelerate the progression of cognitive impairment and dementia. Our current NHLBI-funded Parent proposal on “Circadian regulator of vascular aging” (5R01HL146103) aims to uncover the previously unknown function of the master osteogenic transcriptional factor, Runx2, in regulating vascular smooth muscle cell (VSMC) function during the development of vascular aging. The Parent proposal focuses on the study of arterial stiffness and calcification in the large aortic arteries; and attempts to define the previously unknown regulation of Runx2 by circadian clock-mediated protein O-GlcNAcylation. Studies in the Parent proposal identified increased Runx2 expression in mouse aortas in an age-dependent manner, which was associated with increased pulse wave velocity (PWV), an indicator for arterial stiffness and a predictor for future cardiovascular events. Preliminary studies determined that Runx2 deficiency in SMC inhibited arterial stiffness, and improved cerebral blood flow. Furthermore, mice with SMC- specific Runx2 deletion took less time in finding objects in the water maze test and moved faster in the open field test, suggesting improved cognitive function. These exciting observations suggest a new role played by Runx2 in SMC in regulating cerebral arterial blood flow and cognitive function. Thus, this Supplement application will take advantage of the two new SMC-specific deletion of BMAL1 (clock dysfunction) and OGT (O-GlcNAcylation ablation) mouse models generated from the Parent R01 to uncover the novel function of the BMAL1/OGT/Runx2 signaling cascade in regulating cerebral vascular function and VCID. Furthermore, we will dissect the distinct and overlapping molecular determinates in two vascular systems, aortic and cerebral, using unbiased system biology approaches, which may lead to identification of new signaling cascades and signature cell populations that uniquely regulate cerebral vascular function and VCID; and provide new insights into novel strategies for prevention of age-related vascular disorders, and improving public health and lifespan.