权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Hypertension and neurovascular dysfunction

高血压和神经血管功能障碍

基本信息

批准号：
9915965
负责人：
Costantino Iadecola
金额：
$ 46.61万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915965
关键词：
Address Adult Aging Angiotensin II Antihypertensive Agents Basement membrane Blood - brain barrier anatomy Blood Vessels Bone Marrow Bone Marrow Transplantation Brain Cell model Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chimera organism Chronic Cognition Cognitive Consensus Data Dementia Dichloromethylene Diphosphonate Dose Electron Microscopy Encapsulated Endothelial Cells Functional disorder Gene Deletion Genes Genetic Genetic Models Goals Human Hypertension Impaired cognition Infusion procedures Knowledge Life Link Liposomes Maintenance Mediating Modeling Molecular Morbidity - disease rate Mus NADPH Oxidase Neurons Organ Oxidative Stress Pathogenicity Peptides Perfusion Pericytes Positioning Attribute Predisposition Prevention therapy Process Production Proteins Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Risk Risk Factors Role Side Source Stress Stroke Structure Testing Tight Junctions Uncertainty United States National Institutes of Health Vascular Endothelium Vesicle aged blood lead blood-brain barrier function brain dysfunction burden of illness cellular targeting cerebrovascular cognitive function defined contribution experimental study hypertension treatment insight interest ischemic injury macrophage monocyte mortality neurovascular normotensive novel novel strategies prevent public health relevance receptor response stroke risk therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Hypertension is a leading risk factor for stroke and dementia, but the mechanisms mediating its deleterious effects on the brain remain poorly understood. Hypertension damages the structure and function of cerebral blood vessels increasing the susceptibility of the brain to stroke and cognitive impairment. In particular, hypertension disrupts critical homeostatic mechanisms that assure adequate cerebral perfusion, promoting vascular insufficiency and brain dysfunction. In the hypertension induced by infusion of low doses of angiotensin II (AngII), a peptide involved in human hypertension, or in mice with life-long hypertension on genetic basis (BPH mice), the cerebrovascular dysfunction is mediated by activation of AngII type 1 receptors (AT1R) resulting in vascular oxidative stress produced by a Nox2-containing NADPH oxidase. The cellular target(s) of AngII, its effectors in the vascular wall and the impact of the neurovascular dysfunction on cognition remain to be established and are of great translational relevance. Perivascular macrophages (PVM) are bone marrow derived cells residing in the perivascular space in close apposition to the cerebrovascular basement membrane and express AT1R and Nox2 and, as such, are well positioned to contribute to the cerebrovascular dysfunction induced by AngII-dependent hypertension. The central hypothesis of this application is that PVM are critical cells for the cerebrovascular and cognitive dysfunctio induced by hypertension. To this end, first we will establish whether AngII, infused for 2 weeks, crosses the blood-brain barrier and reaches the PVM in the perivascular space. Second, we will determine whether PVM are required for the cerebrovascular and cognitive alterations induced by AngII infusion. Third, we will determine whether AT1R and Nox2 in PVM are involved in the dysfunction. In parallel studies we will also examine the role of PVM in the cerebrovascular and cognitive dysfunction observed in young and aged mice with life-long hypertension (BPH mice). To achieve these goals we will use state-of-the-art approaches to study neurovascular regulation in combination with bone marrow chimeras and genetic models for cell specific conditional deletion of genes of interest. The findings derived from the proposed studies will fill an obvious gap in our understanding of the cellular mechanisms of the brain dysfunction induced by hypertension, and will provide proof-of-principle that PVM may be a therapeutic target for the devastating effects of hypertension on the brain.

描述（由申请人提供）：高血压是中风和痴呆的主要危险因素，但对介导其对大脑有害影响的机制仍知之甚少。高血压损害脑血管的结构和功能，增加大脑对中风和认知障碍的易感性。特别是，高血压破坏了确保足够脑灌注的关键稳态机制，促进血管功能不全和脑功能障碍。在通过输注低剂量血管紧张素II（AngII）（一种参与人类高血压的肽）诱导的高血压中，或在遗传基础上具有终身高血压的小鼠（BPH小鼠）中，脑血管功能障碍由AngII 1型受体（AT1R）的激活介导，导致由含Nox 2的NADPH氧化酶产生的血管氧化应激。AngII的细胞靶点、血管壁中的效应物以及神经血管功能障碍对认知的影响仍有待建立，并且具有很大的翻译相关性。血管周围巨噬细胞（PVM）是骨髓来源的细胞，位于血管周围空间，与脑血管基底膜紧密贴壁，并表达AT1R和Nox 2，因此，很好地定位于促进AngII依赖性高血压诱导的脑血管功能障碍。本申请的中心假设是PVM是高血压引起的脑血管和认知功能障碍的关键细胞。为此，首先我们将确定输注2周的AngII是否穿过血脑屏障并到达血管周围空间中的PVM。其次，我们将确定血管紧张素II输注引起的脑血管和认知改变是否需要PVM。第三，我们将确定PVM中的AT 1R和Nox 2是否参与了功能障碍。在平行研究中，我们还将研究PVM在患有终身高血压的年轻和老年小鼠（BPH小鼠）中观察到的脑血管和认知功能障碍中的作用。为了实现这些目标，我们将使用最先进的方法来研究神经血管调节与骨髓嵌合体和细胞特异性条件性缺失感兴趣的基因的遗传模型相结合。从拟议研究中得出的结果将填补我们对高血压引起的脑功能障碍的细胞机制的理解存在明显的差距，并将提供PVM可能是高血压对脑的破坏性影响的治疗靶点的原理证明。