Central RAAS and Brain Small Vessel Disease

中枢 RAAS 和脑小血管疾病

基本信息

批准号：
10172988
负责人：
Frank M Faraci
金额：
$ 50.8万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172988
关键词：
Acetates Address Affect Angiotensin II Angiotensin II Receptor Animal Model Area Biology Blood Vessels Brain Cells Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Cognitive deficits Communities Data Dementia Deoxycorticosterone Disease Endothelium Essential Hypertension Exhibits Genetic Models Goals Health Heterogeneity Human Human Genetics Hypertension Impaired cognition Knowledge Literature Mechanics Microvascular Dysfunction Modeling Molecular Target Myocardial Infarction Nitric Oxide Synthase Oxidative Stress PPAR gamma Pathogenesis Pathway interactions Patients Peripheral Pharmacology Process Protein Isoforms Regulation Renin-Angiotensin System Renin-Angiotensin-Aldosterone System Resistance Resources Rho-associated kinase Risk Factors Role Signal Pathway Sodium Chloride Stroke Structure Testing Variant Vasomotor Vasopressins Work arteriole base brain circulation cerebral artery cerebral microvasculature cerebrovascular experimental study genetic approach genetic manipulation global health innovation interest nervous system disorder novel parenchymal arterioles pressure prevent vascular factor

项目摘要

Although the consequences of small vessel disease (SVD) are devastating for brain, there are no specific therapies at present. Knowledge of mechanisms that underlie and might potentially be used to prevent SVD and its effects, which include strokes and cognitive deficits, is very limited. Brain parenchymal arterioles are important resistance vessels and preferential targets of SVD. Hypertension is a the leading risk factor for SVD. For reasons that are not clear, hypertension is a greater risk factor for stroke than for myocardial infarction. Although the brain renin-angiotensin-aldosterone system (RAAS) contributes to hypertension, it is not known if it also affects the local vasculature. In that sense, cerebral vessels may be subjected to both increased intravascular pressure as well as local effects during activation of the brain RAAS. Our overall hypothesis is that the cerebral circulation is affected by the central RAAS and that endothelial peroxisome proliferator-activated receptor-γ (PPARγ) protects against such effects. We propose two Specific Aims. Aim 1 uses two models to determine if activation of the brain RAAS affects function, structure, or mechanics of cerebral arteries and parenchymal arterioles. One is a recent variation of the DOCA-salt model, characterized by activation of the brain RAAS, but suppression of the peripheral RAAS. In the second, the brain RAAS is activated by genetic manipulation. Preliminary data suggest the central RAAS impacts select signaling pathways, vasomotor regulation, and vascular structure. Interestingly, these effects were specific for cerebral vessels. Aim 2 will determine if endothelial PPARγ protects against central RAAS-induced vascular changes via mechanisms that include suppression of angiotensin II receptors, oxidative stress, and the ROCK2 isoform of Rho kinase. Pilot data support this Aim as well. The premise for these studies fit well within the goals of this RFA, focusing on novel mechanisms that underlie SVD during hypertension. The models exhibit features making them representative of a greater percentage of people with essential hypertension compared to more common approaches. Pilot data reveal vascular heterogeneity that contributes to increased susceptability of the brain circulation during hypertension. In summary, the impact of SVD is great, but our understanding of the underlying vascular biology and the impact of hypertension on the brain vasculature in lacking. Using innovative models and approaches, the proposed work will fill gaps identified in the literature and by the scientific community regarding needed advances in our understanding of SVD, vascular biology, and impact of hypertension on the brain vasculature. This area of study has unquestionable relevance to global health. Our sharing of expertise and resources supports a focus on mechanisms of SVD with models and approaches and concepts that are unique.

尽管小血管病（SVD）对大脑造成的后果是毁灭性的，但目前还没有具体的治疗方法。目前的治疗方法。了解潜在的机制并可能用于预防 SVD。它对脑实质小动脉的影响（包括中风和认知缺陷）非常有限。重要的阻力血管和 SVD 的优先目标高血压是 SVD 的主要危险因素。由于尚不清楚的原因，高血压是中风的一个比心肌病更大的危险因素。尽管脑肾素-血管紧张素-醛固酮系统（RAAS）会导致高血压，但它是尚不清楚它是否也会影响局部脉管系统，从这个意义上说，脑血管可能会受到这两种影响。血管内压力增加以及大脑 RAAS 激活期间的局部影响。假设是脑循环受到中枢 RAAS 的影响，并且内皮过氧化物酶体增殖物激活受体-γ (PPARγ) 可防止此类影响。 1 使用两个模型来确定大脑 RAAS 的激活是否会影响大脑的功能、结构或机制脑动脉和实质小动脉是 DOCA-盐模型的最新变体，其特征是激活大脑 RAAS，但抑制外周 RAAS。大脑 RAAS 是通过基因操作激活的，初步数据表明 RAAS 影响选择。信号通路、血管舒缩调节和血管结构。对于脑血管，目标 2 将确定内皮 PPARγ 是否可以预防中枢 RAAS 诱导的损伤。通过抑制血管紧张素 II 受体、氧化应激和 Rho 激酶的 ROCK2 亚型也支持这一目标，这些研究的前提也很合适。在本次 RFA 的目标范围内，重点关注高血压期间 SVD 的新机制。模型所表现出的特征使它们能够代表更大比例的具有基本能力的人与更常见的方法相比，高血压的研究揭示了血管异质性。总而言之，有助于增加高血压期间大脑循环的易感性。 SVD 的研究固然重要，但我们对潜在血管生物学以及高血压对健康的影响的了解利用创新的模型和方法，所提出的工作将填补大脑血管系统的空白。文献和科学界认为我们的理解需要取得进展 SVD、血管生物学以及高血压对脑血管系统的影响。我们分享的专业知识和资源与全球健康有着无可置疑的相关性，支持对这一问题的关注。 SVD 机制具有独特的模型、方法和概念。