Mechanism of Vascular Impairment in Neurocognitive Disorders
神经认知障碍中血管损伤的机制
基本信息
- 批准号:10553093
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAmericanAmyloidAnimal ModelAttentionBiological MarkersBloodBlood - brain barrier anatomyBlood VesselsBlood brain barrier dysfunctionBrainBrain DiseasesBrain PathologyCatabolismCell Culture TechniquesCerebral Amyloid AngiopathyCerebrovascular CirculationCerebrumChronicCognitionComplexDementiaDiseaseDrug TargetingElderlyEndothelial CellsEndotheliumEnzymesEtiologyExpectancyF-ActinFunctional disorderGeneticGoalsHealthHeart DiseasesHemorrhageHomeostasisHumanHypertensionImpaired cognitionImpairmentInflammationInvestigationIschemiaKnockout MiceLaboratoriesMaintenanceMediatingMetabolicMetabolic syndromeMetabolismMissionMutant Strains MiceN,N-dimethylarginineNOS3 geneNeurocognitiveNeuronsNitric OxideNon-Insulin-Dependent Diabetes MellitusObesityOxidation-ReductionPathogenesisPathologicPathologyPeroxonitritePlayPopulationProductionProteinsRegulationReportingResearchRisk FactorsRoleS-NitrosoglutathioneStress FibersStudy modelsSyndromeTherapeuticTransgenic MiceUnited States Department of Veterans AffairsValidationVascular DiseasesVascular EndotheliumVeteransabeta depositionage relatedagedblood-brain barrier disruptionblood-brain barrier functioncerebral hypoperfusioncerebral microvasculaturedesigndimethylargininaseearly onsetendothelial dysfunctionhemodynamicshypoperfusioninhibitorinsightmouse modelmutantneurocognitive disorderneuroinflammationneurovascularnitrosative stresspharmacologictherapeutic targetvascular cognitive impairment and dementiawasting
项目摘要
Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly
including veterans. Since proportion of the elderly population is progressively increasing, VCID has become a
significant problem for elderly citizens, especially veterans. Therefore, the study of this disease is relevant to
veterans’ health and thus the mission of the Veterans Administration. VCID involves multiple risk factors, such
as hypertension, cardiac disease, obesity, and type 2 diabetes mellitus (T2DM). Over 40 million Americans
aged 70 years or older have at least one of these metabolic risk factors, yet we know relatively little about how
these risk factors contribute to VCID.
Recently, elevation of asymmetric dimethylarginine (ADMA) in blood has gained attention as a biomarker and
a risk factor for vascular disease. ADMA catabolism is reduced by decreased expression/activity of its catabolic
enzyme dimethylarginine dimethylaminohydrolase (DDAH) under conditions of vascular disease. Secondly,
DDAH dysfunction and ADMA elevation contribute to dysfunction of endothelial nitric oxide (NO) synthase
(eNOS) leading to vascular and endothelial disease. ADMA uncouples eNOS leading to dysfunction of redox-
based NO metabolism with excessive production of peroxynitrite (ONOOˉ). ADMA is also reported to reduce
cerebral blood flow (CBF) and blood-brain barrier (BBB) dysfunction. While decreased CBF and BBB disruption
have been highly implicated in the pathogenesis of VCID, the role of ADMA in VCID-related pathogenesis, as
well as underlying endothelial/vascular mechanisms are not well understood at present. Therefore, the goal of
proposed study is to investigate ADMA as an intermediary mechanism between the known risk factors and
VCID-related brain pathologies and to evaluate the therapeutic strategies targeting the ADMA-induced
endothelial eNOS/NO dysregulation for VCID associated brain disease.
To understand ADMA-mediated mechanisms in VCID, we have recently investigated the role of ADMA in
vascular and neurocognitive-pathologies in a mouse model of early-onset cerebral amyloid angiopathy (CAA:
Tg-SwDI). CAA is known to promote VCID through a number of mechanisms including inflammation,
hypoperfusion, and loss of BBB function and integrity. From these initial investigations, we discovered that
ADMA overburden during the course of CAA causes an increased BBB dysfunction, loss of brain microvessels,
neuroinflammation, and cognitive decline with increased endothelial nitrosative stress. These findings led us
to hypothesize that overburden of blood or brain ADMA levels, as a result of defective DDAH activity, drives
VCID-related microvascular pathogenesis in the brain by disturbing the vascular/endothelial NO homeostasis.
VCID is a multifactorial and complex disease. At present, therefore, there is no specific animal model that is
considered as the gold standard for assessing VCID pathology and therapeutics. We propose to investigate
the role of ADMA in VICD pathogenesis and underlying mechanisms using two mouse models of CAA and
chronic cerebral hypoperfusion (CCH) which are the most relevant to VCID pathogenesis.
Specific Aim 1: To investigate the role of impaired ADMA catabolism in VCID-related pathologies: Studies
are proposed to assess the role of ADMA overburden and DDAH dysfunction as disease modifying factors and
thus therapeutic targets for VCID-associated vascular and neurocognitive pathologies using the pharmacological
(exogenous ADMA treatment) and genetic (use of DDAH1-Tg and DDAH1-Ko mice) approaches.
Specific Aim 2: To investigate the role of imbalanced NO metabolism (ONOOˉ > GSNO) in ADMA-
induced cerebro-microvascular dysfunction: Studies are designed to investigate the mechanism(s)
underlying ADMA-induced dysregulation of eNOS activity in brain microvessels and associated vascular
disease, specifically, the role of ADMA in imbalance of NO metabolism to ONOOˉ vs. S-nitrosoglutathione
(GSNO), which play opposing roles in maintenance of brain microvessel endothelial barrier integrity.
血管性认知障碍和痴呆(VCID)是老年痴呆最常见的病因
项目成果
期刊论文数量(0)
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Avtar K Singh其他文献
LOW DOSE ZIDOVUDINE (ZDV) REDUCES MEDIUM AND LONG CHAIN FATTY ACID OXIDATION IN PREGNANT AND NEONATAL RATS. † 1033
- DOI:
10.1203/00006450-199604001-01055 - 发表时间:
1996-04-01 - 期刊:
- 影响因子:3.100
- 作者:
George M Johnson;Mahesh Gupta;Karl Krember;Avtar K Singh;Inderjit Singh - 通讯作者:
Inderjit Singh
FATPY ACID METABOLISM IN REYE'S SYNDROME
雷耶综合征中的脂肪酸代谢
- DOI:
10.1203/00006450-198704010-01003 - 发表时间:
1987-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Inderjit Singh;Yoshihiro Yoshida;Avtar K Singh;Fred W Mecklenberq;C P Darby - 通讯作者:
C P Darby
5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuates the expression of LPS- and Aβ peptide-induced inflammatory mediators in astroglia
- DOI:
10.1186/1742-2094-2-21 - 发表时间:
2005-09-20 - 期刊:
- 影响因子:10.100
- 作者:
Kamesh R Ayasolla;Shailendra Giri;Avtar K Singh;Inderjit Singh - 通讯作者:
Inderjit Singh
Avtar K Singh的其他文献
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{{ truncateString('Avtar K Singh', 18)}}的其他基金
Mechanism of Vascular Impairment in Neurocognitive Disorders
神经认知障碍中血管损伤的机制
- 批准号:
10343797 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8398957 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
- 批准号:
8458156 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8141069 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
- 批准号:
8259741 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8696815 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
- 批准号:
8652841 - 财政年份:2011
- 资助金额:
-- - 项目类别:














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