Vascular mechanisms of inhibition of sEH as a novel therapy for AD/ADRD
抑制 sEH 作为 AD/ADRD 新疗法的血管机制
基本信息
- 批准号:10525694
- 负责人:
- 金额:$ 172.04万
- 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:2022-08-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease therapyAnimal ModelAnimalsAnti-Inflammatory AgentsArachidonic AcidsAtlasesBiologyBlood - brain barrier anatomyBlood VesselsBlood capillariesBrainCYP2J2 geneCapillary Endothelial CellCell membraneCerebrovascular CirculationCerebrovascular DisordersCerebrovascular systemCerebrumChronicClinical TrialsCognitionCognitiveCognitive deficitsDiabetes MellitusDietary FatsDiseaseEndotheliumEnzymesEpoxide hydrolaseExhibitsExtravasationFemaleFoundationsFunctional disorderGenesGeneticGlycolsHealthcareHippocampus (Brain)HomeostasisHumanHyperemiaImpaired cognitionImpairmentIn VitroInflammationIsomerismKnowledgeLinkLinoleic AcidsLungMusMutationNerve DegenerationNeuronsPathway interactionsPatientsPerfusionPhenotypePhosphatidylinositol 4,5-DiphosphatePhospholipase A2PlayPotassiumRattusRegulationReportingRoleTestingTissuesTranslatingTranslationsVascular PermeabilitiesVasodilationarteriolebaseblood-brain barrier permeabilizationcerebral arterycerebral capillarycerebral hypoperfusioncerebrovascularcognitive disabilitycognitive enhancementcognitive functiondiabeticgenome wide association studyglobal healthhypoperfusionimprovedinhibitorlinoleatesmalemiddle cerebral arteryneglectneurovascular unitnew therapeutic targetnovel therapeuticsparenchymal arteriolesprecision medicinepreventprotective effectresponsesextreatment trialvascular contributions
项目摘要
Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) is an emerging global health
care crisis. However, underlying mechanisms have not been understood well enough for translation to precision
medicine. Understanding vascular contribution to AD/ADRD is imperative since increasing evidence suggests
AD and diabetic (DM)-related ADRD are associated with brain hypoperfusion, and 67% of AD GWAS genes are
expressed in the cerebral vasculature. Recent studies demonstrated that reduction of soluble epoxide hydrolase
(sEH) is beneficial to cognition in AD, DM-ADRD, and cerebral hypoperfusion animal models due to its anti-
inflammatory and neuronal protective effects, but vascular contribution has been neglected. sEH is an enzyme
that transforms arachidonic acid (AA)-derived EETs and linoleic acid (LA)-derived EpOMEs to their
corresponding diols DHETs and DiHOMEs, respectively. Changes in oxylipins, such as the elevated ratio of
DHETs/EETs and DiHOMEs/EpOMEs, were found in AD mice and ADRD patients. We preliminary found
that SNPs in genes (CYP2J2, 2C8, 2C9) encoding enzymes that catalyze AA and LA to EETs and EpOMEs,
and EPHX2 encoding sEH are linked with AD in the ARIC-NCS. We also found that a highly selective sEH
inhibitor (sEHi) TPPU reversed cognitive disability, impaired myogenic response (MR) and autoregulation of
cerebral blood flow (CBF), and neurovascular unit (NVU) dysfunction in DM-ADRD and AD rats. Moreover,
AD/ADRD rats displayed brain hypoperfusion, enhanced blood-brain barrier (BBB) leakage, neurodegeneration,
and reduced brain Kir2.1 activity that has been reported to associate with reduced PIP2 levels in cerebral capillary
endothelial cells due to enhanced PLA2 activity. This proposal will test the HYPOTHESIS that inhibition of sEH
synergistically modulates the PLA2-AA-EETs-DHETS and PLA2-LA-EpOMEs-DiHOMEs pathways to reverse
cognitive impairments and enhance brain perfusion by ameliorating CBF autoregulation, maintaining BBB and
NVU function. We will compare vascular function (MR, CBF autoregulation, and functional hyperemia), AD
phenotypes, regional brain levels of PLA2, sEH, PlP2, Kir2.1, and oxylipins in TPPU-treated both sexes of DM-
ADRD and AD rats. We will also compare vascular responses to isomer mixtures of EETs/DHETs, and
EpOMEs/DiHOMEs in cerebral arteries and arterioles, and vasodilation responses to elevated potassium and
isomer mixtures of oxylipins in arterioles-capillaries isolated from both sexes of control, AD, and ADRD rats to
further explore the specific pathways that are affected by inhibition of sEH. This project will address critical
knowledge gaps of the vascular contribution of sEHi on cognitive protection and the “next steps” in explaining
the biology of the catalytic activity of the sEH. Results generated from this proposal should lay the foundation for
the discovery of new drugs targeting these pathways to reverse cerebral vascular dysfunction to prevent the
onset and slow the progression of AD/ADRD.
.
阿尔茨海默病和阿尔茨海默病及相关痴呆(AD/ADRD)是一个新兴的全球性健康问题
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Fan Fan', 18)}}的其他基金
Adducin, actin cytoskeleton and cognitive impairments
内收蛋白、肌动蛋白细胞骨架和认知障碍
- 批准号:
9897521 - 财政年份:2019
- 资助金额:
$ 172.04万 - 项目类别:
Adducin, actin cytoskeleton and cognitive impairments
内收蛋白、肌动蛋白细胞骨架和认知障碍
- 批准号:
10343669 - 财政年份:2019
- 资助金额:
$ 172.04万 - 项目类别:
Adducin, actin cytoskeleton and cognitive impairments
内收蛋白、肌动蛋白细胞骨架和认知障碍
- 批准号:
10092053 - 财政年份:2019
- 资助金额:
$ 172.04万 - 项目类别:
Animal model of impaired autoregulation for study of age related vascular cognitive impairment
用于研究年龄相关血管认知障碍的自动调节受损动物模型
- 批准号:
9197938 - 财政年份:2016
- 资助金额:
$ 172.04万 - 项目类别:
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