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 脑血管内皮功能障碍会损害整个大脑的血液，并且是年龄的制造商 相关的认知障碍，例如阿尔茨海默氏病（AD）。大约有620万美国人居住 使用AD，超过95％的患者超过65岁；一个可能会翻一番的人群 2050。血管网络的脑血管内皮坐标用于输送氧 以及根据代谢需求的整个脑组织的营养。使用全面，整合和 纵向研究方法，我们努力划定并机械澄清内皮功能障碍 在APOEɛ4（AIM 1）的存在下，涉及与年龄相关痴呆的进展以及如何发展 AD病理学的进步影响脑血管内皮功能对内皮功能障碍 （目标2）。调节血液流向和整个大脑的中心途径，尤其是在 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）和内向切除（KIR2.X）亚型]。特别是我们最近的 已发布的数据表明，脑血管内皮Kir2.x通道中存在性无关的降低 在小鼠模型中均具有进步的年龄和AD病理的功能。此外，我们的初步数据证明了 使用甲基β-环糊精选择性地去除膜胆固醇 渠道功能与年轻，健康状况或更高的频道功能。那就是我们将检验的中心假设，即 由细胞胆固醇引起的内皮内皮KIR通道功能的损害脑血管造成的损伤 痴呆症的衰老和发展。目的利用了离体的创新整合（孤立的大脑 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通道过表达）方法 全面检验这一假设。调查研究团队包括 内皮功能，血管衰老，脑血管生理/病理学和胆固醇调节 内皮K+通道。动物模型需要衰老的内皮细胞特异性kir2.1 +/-＆kir2.1 - / - ，apoEɛ2 /ɛ3 / ɛ4靶向替换和3XTG-AD与相对野生型小鼠。以这种方式，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的人 脑老化和广告的途径，同时专注于内皮kir2.x通道作为新型治疗靶点 药理学和基因疗法。我们将追求来自分子的K+通道活动的微调 对整个生物体的方法；通过治疗来调和分子机制。理想的结果是找到 并处理结构和功能性血管的生理学和病理学之间的精确过渡 “签名”随着年龄和广告相关痴呆的渐进阶段的行为改变。

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