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.

项目概要/摘要 脑血管内皮功能障碍会损害整个大脑的血流，是年龄增长的一个致病因素。 大约有 620 万美国人患有阿尔茨海默病 (AD) 等相关认知障碍。 因此，超过 95% 的 AD 患者年龄超过 65 岁，这一数字可能会增加一倍； 2050.脑血管内皮协调血管网络的血管反应性以输送氧气 以及整个脑组织的营养物质按照代谢需求进行全面、综合和利用。 通过纵向研究方法，我们努力描述并从机制上阐明内皮功能障碍如何 在 ApoE Ɛ4 存在的情况下，先于并伴随年龄相关性痴呆的进展（目标 1）以及如何 AD病理学的进展影响脑血管内皮功能导致内皮功能障碍 （目标 2）调节流向大脑和整个大脑的血流的中心通路，特别是在大脑中。 微循环，涉及由内皮 K+ 通道功能定义的血管舒张信号通路 [Ca2+激活（SKCa/IKCa；KCa2.3/KCa3.1）和内向整流（KIR2.x）亚型尤其是我们最近的亚型]。 已发表的数据表明，脑血管内皮 KIR2.x 通道存在与性别无关的减少 此外，我们的初步数据表明，其在小鼠模型中对年龄增长和 AD 病理学具有重要作用。 使用甲基 β-环糊精温和去除膜胆固醇可选择性恢复 KIR2.x（相对于 SKCa/IKCa） 因此，我们将检验中心假设： 细胞胆固醇引起的内皮 KIR 通道功能受损是脑血管疾病的基础 衰老和痴呆症的发展利用离体（离体大脑）的创新整合。 动脉/小动脉，新鲜分离的内皮），体内（脑灌注，充血，行为），和 介入（脂质调节、脑内皮 KIR2.1 通道过度表达）方法 全面检验这一假设。调查研究小组包括生物物理学专家。 内皮功能、血管老化、脑血管生理/病理和胆固醇调节 内皮 K+ 通道动物模型需要衰老内皮细胞特异性 KIR2.1+/- 和 KIR2.1-/-、ApoE Ɛ2 / Ɛ3 / Ɛ4 靶向替代和 3xTg-AD 与相应野生型小鼠的研究策略。 将是第一个描述由细胞胆固醇变化引起的内皮功能障碍作为病因的人 脑衰老和 AD 的通路，同时关注内皮 KIR2.x 通道作为新的治疗靶点 我们将追求从分子层面对 K+ 通道活性进行微调。 整个有机体的方法；使分子机制与治疗相协调。 并治疗生理学和病理学之间的精确转变，将结构性和功能性血管结合起来 围绕年龄和 AD 相关痴呆进行性阶段的行为改变的“特征”。

项目成果

Editorial: Transient receptor potential channels (TRP): signal transduction.

• DOI: 10.3389/fmolb.2023.1201614
• 发表时间: 2023
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5

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