Novel regulation of vascular dementia

血管性痴呆的新调节

• 批准号: 10716861
• 负责人: Yabing Chen
• 金额: $ 52.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716861
• 关键词: APP-PS1; Acceleration; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Aneurysm; Animal Model; Aorta; Apolipoprotein E; Arteries; Atherosclerosis; Biochemical; Bioinformatics; Blood Vessels; Blood flow; Brain; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Clinical; Clinical Management; Clinical Treatment; Coronary Arteriosclerosis; Dementia; Development; Disease; Elderly; Genetic Transcription; Goals; Health; High Fat Diet; Human; Hypertension; Impaired cognition; In Vitro; Ischemic Stroke; Knowledge; Link; Localized Lesion; Mediating; Molecular; Mus; Nutrient; Organ; Outcome; Oxygen; Pathogenesis; Pathology; Peripheral arterial disease; Phenotype; Play; Population; Proteomics; Quality of life; Regulation; Reporting; Resources; Role; Serum Response Factor; Signal Transduction; Smooth Muscle Myocytes; Stroke; Systemic disease; Testing; Tissues; Up-Regulation; Vascular Dementia; Vascular Diseases; Vascular calcification; age related; arterial stiffness; atherosclerosis risk; brain dysfunction; calcification; cardiovascular risk factor; cerebrovascular; cerebrovascular pathology; cognitive function; genetic risk factor; genome-wide analysis; human tissue; improved; in vivo; insight; molecular array; mouse model; multidisciplinary; multiple omics; normal aging; novel; novel strategies; pre-clinical; risk variant; single-cell RNA sequencing; synergism; tool; transcription factor; treatment strategy

Abstract Vascular dementia (VaD) is the second most common cause of dementia, often triggers progressive cognitive impairment similar to that of Alzheimer’s disease (AD). The current treatment strategies focusing on local lesions for AD and dementia have not led to satisfactory outcomes. Therefore, comprehensively understanding of the pathogenesis of VaD and AD is urgently required to address the unmet scientific and clinical needs. Vascular pathologies across all vasculature have also been linked to VaD and AD. Most notably, atherosclerosis, stroke and hypertension accelerate the progression of cognitive impairments and dementia of all causes. Multiple large genome-wide studies identify the atherosclerosis risk gene apolipoprotein E (APOE) as a strong genetic risk factor for AD. However, despite shared genetic risk factors, atherosclerosis and AD are often separated in clinical management and mechanistic studies. Pan-vascular diseases represented by coronary artery disease, ischemic stroke, aneurysm and peripheral artery disease are all associated with VaD, thus, investigating pan-vascular changes that impact cognitive functions may open up new avenues to understand VaD and AD. The current application represents our long-term goals to uncover novel mechanisms linking vascular dysfunctions in the cardio and cerebrovascular systems to VaD and AD. Our effort has led to the discovery of a new role of the Runt-related transcription factor 2 (Runx2) in regulating both aortic and cerebral vascular pathologies and cognitive functions. We and others previously reported that Runx2 is an integral regulator for vascular calcification. Our preliminary studies identified novel function of Runx2 in regulating atherosclerosis, arterial stiffness, cerebral blood flow and cognitive function in mice; and uncovered upregulation of Runx2 in aging, atherosclerosis and AD mice as well as in human AD/VaD tissues. Single cell RNA sequencing analysis further discovered a novel regulation of Runx2 on SMC phenotypic switch, beyond its known activity in promoting SMC calcification. With an array of molecular, biochemical, proteomics and bioinformatics approaches, preliminary studies uncovered Runx2 interaction with an essential contractile SMC regulator, serum response factor (SRF), supporting a novel Runx2/SRF regulatory network in SMC phenotypic switch and calcification. Elucidating the novel function of Runx2 and Runx2-dependent signaling in regulating VaD will provide new insights to fill the knowledge gaps, which may lead to novel strategies for clinical management or treatment of VaD and AD.

抽象的 血管性痴呆 (VaD) 是痴呆的第二常见原因，经常引发进行性痴呆 认知障碍与阿尔茨海默病（AD）相似，目前的治疗策略主要集中在认知障碍。 AD和痴呆的局部病变尚未取得令人满意的结果。 迫切需要了解 VaD 和 AD 的发病机制，以解决未满足的科学和临床问题 所有脉管系统的血管病变也与 VaD 和 AD 有关。 动脉粥样硬化、中风和高血压会加速认知障碍和痴呆的进展 多项大型全基因组研究确定了动脉粥样硬化风险基因载脂蛋白 E (APOE)。 然而，尽管有共同的遗传危险因素，动脉粥样硬化和 AD 却是共同的遗传危险因素。 以泛血管疾病为代表 冠状动脉疾病、缺血性中风、动脉瘤和外周动脉疾病都与 VaD 有关， 因此，研究影响认知功能的全血管变化可能会开辟新的途径 了解 VaD 和 AD。当前的应用代表了我们发现新机制的长期目标。 将心脑血管系统的血管功能障碍与 VaD 和 AD 联系起来。 发现 Runt 相关转录因子 2 (Runx2) 在调节主动脉和大脑中的新作用 我们和其他人之前报道过 Runx2 是一个不可或缺的因素。 我们的初步研究确定了 Runx2 在调节中的新功能。 小鼠的动脉粥样硬化、动脉僵硬度、脑血流量和认知功能以及未发现的上调； Runx2 在衰老、动脉粥样硬化和 AD 小鼠以及人类 AD/VaD 组织中的作用。 测序分析进一步发现了 Runx2 对 SMC 表型转换的新调控，超出了已知的调控范围 通过一系列分子、生化、蛋白质组学和生物信息学研究，促进 SMC 钙化。 方法，初步研究发现 Runx2 与重要的收缩 SMC 调节因子血清相互作用 响应因子 (SRF)，支持 SMC 表型开关中的新型 Runx2/SRF 调节网络 阐明 Runx2 和 Runx2 依赖性信号传导在调节 VaD 中的新功能将 提供新的见解来填补知识空白，这可能会带来新的临床管理策略或 VaD 和 AD 的治疗。