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
基本信息
- 批准号:10610943
- 负责人:
- 金额:$ 68.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3xTg-AD mouseAbbreviationsAgeAge FactorsAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAmericanAnimal ModelApolipoprotein EArteriesBehaviorBehavioralBiophysicsBloodBlood VesselsBlood flowBrainCerebrovascular CirculationCerebrovascular PhysiologyCerebrovascular systemCerebrumCholesterolCholesterol HomeostasisCognitionCognitiveCoupledDataDementiaDevelopmentElderlyEndothelial CellsEndotheliumExcisionExperimental DesignsFunctional disorderGoalsHealthHumanHuman GeneticsHyperemiaImpairmentInterventionIon ChannelKir2.1 channelKnock-outLipidsLongevityMediatorMembraneMemoryMetabolicMicrocirculationMolecularNeurodegenerative DisordersNutrientOrganOutcomeOxygenPathologicPathologyPathway interactionsPatientsPerfusionPharmacologyPhasePhysical activityPhysiologicalPhysiologyPlayPotassium ChannelPredispositionProcessPropertyPublishingQuality of lifeRegulationRelaxationResearchResearch Project GrantsResistanceRisk FactorsRoleSignal PathwaySkeletal MuscleSmooth Muscle MyocytesSocietiesTestingTherapeutic InterventionTransgenic AnimalsVariantVascular DiseasesVasodilationWhole OrganismWild Type Mouseage relatedage related cognitive disorderaging brainarteriolebrain pathwaybrain tissuecerebral arterycerebrovascularcerebrovascular pathologyeffective therapyendothelial dysfunctionfunctional improvementgene therapygenetic varianthuman old age (65+)improvedin vivoinnovationmethyl-beta-cyclodextrinmouse modelneurovascular couplingnew therapeutic targetnoveloverexpressionresponsesexsocialtherapeutic target
项目摘要
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
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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
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ERIK JOSEF BEHRINGER其他文献
ERIK JOSEF BEHRINGER的其他文献
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{{ truncateString('ERIK JOSEF BEHRINGER', 18)}}的其他基金
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:
10440055 - 财政年份:2022
- 资助金额:
$ 68.18万 - 项目类别:
Impact of aging on calcium and electrical signaling in microvascular endothelium
衰老对微血管内皮钙和电信号传导的影响
- 批准号:
9057785 - 财政年份:2015
- 资助金额:
$ 68.18万 - 项目类别:
Impact of aging on calcium and electrical signaling in microvascular endothelium
衰老对微血管内皮钙和电信号传导的影响
- 批准号:
9132663 - 财政年份:2015
- 资助金额:
$ 68.18万 - 项目类别:
Impact of aging on calcium and electrical signaling in microvascular endothelium
衰老对微血管内皮钙和电信号传导的影响
- 批准号:
8673946 - 财政年份:2014
- 资助金额:
$ 68.18万 - 项目类别:
Regulation of conducted hyperpolarization in microvascular endothelial cell tubes
微血管内皮细胞管传导超极化的调节
- 批准号:
8316463 - 财政年份:2011
- 资助金额:
$ 68.18万 - 项目类别:
Regulation of conducted hyperpolarization in microvascular endothelial cell tubes
微血管内皮细胞管传导超极化的调节
- 批准号:
8203192 - 财政年份:2011
- 资助金额:
$ 68.18万 - 项目类别:
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