Administrative Supplement to Award "Circadian regulation of vascular aging"

“血管老化的昼夜节律调节”奖行政补充

• 批准号: 10283788
• 负责人: JOHN C CHATHAM
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-18 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283788
• 关键词: ARNTL gene; Ablation; Administrative Supplement; Aging; Alzheimer' s Disease; Aorta; Arteries; Atherosclerosis; Award; Blood Vessels; Blood flow; Brain; Brain region; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; ChIP-seq; Clinical; Clinical Research; Clock protein; Complement; Data; Dementia; Development; Disease; Event; Foundations; Functional disorder; Funding; Future; Homeostasis; Hypertension; Image; Impaired cognition; Impairment; Incidence; Infarction; Knowledge; Lead; Lesion; Link; Longevity; Mediating; Midbrain structure; Molecular; Molecular Profiling; Molecular Structure; Mus; National Heart, Lung, and Blood Institute; Nutrient; Oxygen; Parents; Pathology; Peripheral arterial disease; Physiologic pulse; Play; Population; Prevention; Prevention strategy; Proteins; Public Health; Regulation; Reporting; Risk Factors; Role; Science; Signal Transduction; Smooth Muscle Myocytes; Stroke; Structure; Systems Biology; Testing; Time; Vascular Dementia; Vascular Diseases; Vascular Smooth Muscle; Vascular System; Vascular calcification; age related; arterial stiffness; calcification; cell type; cerebral artery; cerebrovascular; circadian; circadian pacemaker; circadian regulation; clinical application; cognitive function; design; epidemiology study; experimental study; field study; improved; in vivo; insight; meetings; mouse model; novel; novel strategies; osteogenic; relating to nervous system; single-cell RNA sequencing; transcription factor; transcriptome sequencing; transcriptomics; vascular cognitive impairment and dementia; water maze

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.

翻译后摘要：老化是各种疾病的主要危险因素，特别是阿尔茨海默氏痴呆症（AD）， 心血管疾病血管对认知障碍和痴呆（VCID）的贡献是第二大 AD后痴呆的常见原因。中脑区域的血管损伤会导致渐进性认知障碍 血管性痴呆常与阿尔茨海默病斑块共存。因此，我们认为， 更好地了解VCID可以提供新的解决方案，改善VCID的预防和管理， AD.脑血管功能障碍，以脑血管病变和梗死为特征，限制血液流动， 氧气和营养供应到大脑，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硬化与VCID相关，并加速认知功能障碍的进展。 损伤和痴呆。我们目前NHLBI资助的关于“血管的昼夜节律调节器”的家长提案 老化”（5 R 01 HL 146103）旨在揭示以前未知的主成骨细胞的功能， 转录因子Runx 2在发育过程中调节血管平滑肌细胞（VSMC）功能 血管老化的迹象Parent提案的重点是研究大动脉硬化和钙化， 主动脉;并试图定义以前未知的调节Runx 2的昼夜节律钟介导的， 蛋白质O-GlcNAc化。亲本提案中的研究确定了小鼠睾丸中Runx 2表达的增加 以年龄依赖的方式，这与脉搏波速度（PWV）增加有关，PWV是 动脉硬化和未来心血管事件的预测因子。初步研究确定Runx 2 SMC缺乏抑制动脉硬化，改善脑血流量。此外，SMC- 特异性Runx 2缺失在水迷宫测试中寻找物体所需的时间更短，在开阔视野中移动更快 测试，表明认知功能改善。这些令人兴奋的观察表明Runx 2扮演了新角色 SMC在调节脑动脉血流和认知功能中的作用。因此，本补充申请将 利用两种新的SMC特异性缺失BMAL 1（生物钟功能障碍）和OGT（O-GlcNAcylation 消融）小鼠模型，以揭示BMAL 1/OGT/Runx 2的新功能 信号级联调节脑血管功能和VCID。此外，我们将剖析不同的 和重叠的分子决定因素在两个血管系统，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签名细胞群 其独特地调节脑血管功能和VCID;并提供了对新策略的新见解， 预防与年龄有关的血管疾病，改善公众健康和寿命。