Role of Endothelial K+ Channels in Age-Related Dementia

内皮钾离子通道在年龄相关性痴呆中的作用

• 批准号: 10610943
• 负责人: ERIK JOSEF BEHRINGER
• 金额: $ 68.18万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610943
• 关键词: 3xTg-AD mouse; Abbreviations; Age; Age Factors; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Animal Model; Apolipoprotein E; Arteries; Behavior; Behavioral; Biophysics; Blood; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Cerebrovascular Physiology; Cerebrovascular system; Cerebrum; Cholesterol; Cholesterol Homeostasis; Cognition; Cognitive; Coupled; Data; Dementia; Development; Elderly; Endothelial Cells; Endothelium; Excision; Experimental Designs; Functional disorder; Goals; Health; Human; Human Genetics; Hyperemia; Impairment; Intervention; Ion Channel; Kir2.1 channel; Knock-out; Lipids; Longevity; Mediator; Membrane; Memory; Metabolic; Microcirculation; Molecular; Neurodegenerative Disorders; Nutrient; Organ; Outcome; Oxygen; Pathologic; Pathology; Pathway interactions; Patients; Perfusion; Pharmacology; Phase; Physical activity; Physiological; Physiology; Play; Potassium Channel; Predisposition; Process; Property; Publishing; Quality of life; Regulation; Relaxation; Research; Research Project Grants; Resistance; Risk Factors; Role; Signal Pathway; Skeletal Muscle; Smooth Muscle Myocytes; Societies; Testing; Therapeutic Intervention; Transgenic Animals; Variant; Vascular Diseases; Vasodilation; Whole Organism; Wild Type Mouse; age related; age related cognitive disorder; aging brain; arteriole; brain pathway; brain tissue; cerebral artery; cerebrovascular; cerebrovascular pathology; effective therapy; endothelial dysfunction; functional improvement; gene therapy; genetic variant; human old age (65+); improved; in vivo; innovation; methyl-beta-cyclodextrin; mouse model; neurovascular coupling; new therapeutic target; novel; overexpression; response; sex; social; therapeutic target

Project Summary/Abstract Cerebrovascular endothelial dysfunction impairs blood flow throughout the brain and is a causative factor of age- related cognitive disorders such as Alzheimer’s disease (AD). Approximately 6.2 million Americans are living with AD, whereby more than 95% of patients are over the age of 65; a demographic that will likely double by 2050. Cerebrovascular endothelium coordinates vasoreactivity of blood vessel networks for delivery of oxygen and nutrients throughout brain tissue in accord with metabolic demand. Using a comprehensive, integrative and longitudinal research approach, we endeavor to delineate and mechanistically clarify how endothelial dysfunction precedes and accompanies progression of age-related dementia in the presence of ApoE Ɛ4 (Aim 1) and how the advancement of AD pathology impacts cerebrovascular endothelial function towards endothelial dysfunction (Aim 2). A central pathway for modulation of blood flow to and throughout the brain, but particularly in the microcirculation, involves vasodilatory signaling pathways defined by the function of endothelial K+ channels [Ca2+-activated (SKCa/IKCa; KCa2.3/KCa3.1) and inward-rectifying (KIR2.x) subtypes]. In particular, our recently published data indicate that there are sex-independent reductions in cerebrovascular endothelial KIR2.x channel function with both advancing age and AD pathology in mouse models. Further, our preliminary data demonstrate that mild removal of membrane cholesterol using methyl β-cyclodextrin selectively restores KIR2.x (vs. SKCa/IKCa) channel function to that of young, healthy conditions or better. Thus, we will test the central hypothesis that impairment in endothelial KIR channel function caused by cellular cholesterol underlies cerebrovascular aging and development of dementia. The Aims utilize an innovative integration of ex vivo (isolated cerebral arteries/arterioles, freshly isolated endothelium), in vivo (cerebral perfusion, hyperemia, behavior), and interventional (lipid regulation, cerebral endothelial KIR2.1 channel overexpression) approaches to comprehensively test this hypothesis. The investigating research team includes experts in the biophysics of endothelial function, vascular aging, cerebrovascular physiology/pathology, and cholesterol modulation of endothelial K+ channels. Animal models entail aging endothelial cell-specific KIR2.1+/- & KIR2.1-/-, ApoE Ɛ2 / Ɛ3 / Ɛ4 targeted replacement and 3xTg-AD vs. respective wild-type mice. In such manner, the Research Strategy will be the first to delineate endothelial dysfunction, caused by changes in cellular cholesterol, as a causative pathway of brain aging and AD while focusing on endothelial KIR2.x channels as a novel therapeutic target for pharmacology and gene therapies. We will pursue fine-tuning of K+ channel activity spanning from molecular approaches to the whole organism; reconciling molecular mechanisms with therapy. The ideal outcome is to find and treat precise transitions between physiology and pathology uniting structural and functional vascular “signatures” with behavioral alterations surrounding progressive phases of age- and AD-related dementia.

项目摘要/摘要 脑血管内皮细胞功能障碍损害整个大脑的血液流动，是年龄的一个原因- 相关的认知障碍，如阿尔茨海默病(AD)。大约有620万美国人生活在 阿尔茨海默病，超过95%的患者年龄在65岁以上；这一人口统计数字可能会在 2050年。脑血管内皮细胞协调供氧血管网的血管反应性 以及脑组织中的营养物质符合新陈代谢需求。使用全面、综合和 纵向研究方法，我们努力描绘和机械地阐明内皮功能障碍是如何 在ApoEƐ4存在的情况下，老年性痴呆进展的先兆和伴发(目标1)以及如何 阿尔茨海默病病理进展对脑血管内皮细胞功能的影响 (目标2)。调节流向和贯穿大脑的血流量的中心途径，尤其是在 微循环，涉及内皮K+通道功能所决定的血管扩张信号通路 [钙激活(SKCa/IKCa；KCa2.3/KCa3.1)和内向整流(KIR2.x)亚型]。尤其是我们最近 已发表的数据表明，脑血管内皮细胞KIR2.x通道存在性别无关的减少 在小鼠模型中的作用与增龄和AD病理有关。此外，我们的初步数据表明 用甲基β-环糊精温和去除膜胆固醇选择性地恢复KIR2.x(vs SKCa/IKCa) 经络功能要达到年轻、健康状态或更好。因此，我们将检验中心假设 细胞胆固醇致内皮细胞KIR通道功能受损是脑血管疾病的基础 衰老与痴呆症的发展。AIMS利用了体外(隔离大脑)的创新集成 动脉/小动脉，新鲜分离的内皮细胞)，体内(脑灌注，充血，行为)，以及 介入性(脂质调节，脑内皮细胞Kir2.1通道过表达)途径 全面检验这一假设。调查研究小组包括生物物理学方面的专家。 血管内皮功能、血管衰老、脑血管生理学/病理学和胆固醇调节 内皮K+通道。衰老内皮细胞特异性Kir2.1+/-和Kir2.1-/-、载脂蛋白EƐ2/Ɛ3/的动物模型 Ɛ4靶向替换和3xTg-AD与各自的野生型小鼠。在这种情况下，研究战略 将第一个描述由细胞胆固醇变化引起的内皮功能障碍 脑老化与阿尔茨海默病的通路及内皮KIR2.x通道作为新的治疗靶点 药理学和基因疗法。我们将从分子水平上追求K+通道活性的微调 针对整个生物体的方法；使分子机制与治疗相协调。理想的结果是找到 并治疗生理和病理之间的精确过渡，将结构血管和功能血管统一起来 随着年龄和AD相关痴呆症进行性阶段的行为改变而出现的“特征”。

项目成果

PNA5, A Novel Mas Receptor Agonist, Improves Neurovascular and Blood-Brain-Barrier Function in a Mouse Model of Vascular Cognitive Impairment and Dementia.

PNA5 是一种新型 Mas 受体激动剂，可改善血管认知障碍和痴呆小鼠模型的神经血管和血脑屏障功能。

• DOI: 10.14336/ad.2023.0928
• 发表时间: 2023
• 期刊: Aging and disease
• 影响因子: 7.4
• 作者: Hoyer-Kimura,Christina;Hay,Meredith;Konhilas,JohnP;Morrison,HelenaW;Methajit,Methawasin;Strom,Joshua;Polt,Robin;Salcedo,Victoria;Fricks,JoshuaP;Kalya,Anjna;Pires,PauloW
• 通讯作者: Pires,PauloW