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.

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