Role of Nrf2 and Cellular Senescence in the brainstem in obesity-induced sympathoexcitation

Nrf2 和脑干细胞衰老在肥胖引起的交感神经兴奋中的作用

• 批准号: 9813060
• 负责人: Madhan Subramanian
• 金额: $ 44.25万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813060
• 关键词: Address; Affect; Anti-inflammatory; Antihypertensive Agents; Antioxidants; Brain Stem; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Aging; Cells; Chronic; Cytoprotection; DNA Damage; Data; Developing Countries; Development; Environment; Essential Hypertension; Framingham Heart Study; Functional disorder; Gene Expression; Gene Transfer; Growth; Hypertension; Imaging Techniques; Impairment; Incidence; Individual; Inflammatory; Intervention; Kidney; Knockout Mice; Link; Measures; Mediating; Methods; Molecular; Mus; Muscle; National Health and Nutrition Examination Survey; Nerve; Obesity; Obesity associated cardiovascular disease; Obesity associated disease; Oklahoma; Output; Overweight; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Prevention; Process; Quality of life; Reflex action; Regulation; Research; Resistant Hypertension; Risk Estimate; Risk Factors; Role; Signal Transduction; State Government; Stress; Sympathetic Nervous System; System; Techniques; Telemetry; Testing; Tissues; Transgenic Mice; United States; Universities; Viral Vector; Woman; Work; adult obesity; base; blood pressure regulation; cardiovascular risk factor; cellular imaging; cost; genetic manipulation; graduate student; hypertension treatment; inflammatory milieu; innovation; men; mouse model; neurogenic hypertension; neuroinflammation; neurophysiology; new therapeutic target; novel; novel strategies; overexpression; premature; programs; senescence; targeted treatment; training opportunity; trend; undergraduate student; vector-induced

Obesity is a major risk factor for the development of cardiovascular diseases including hypertension, but the mechanisms are unclear. Accumulating evidence suggests that increases in sympathetic nerve activity (SNA) play a crucial role in the pathophysiology of obesity-induced hypertension. The rostral ventrolateral medulla (RVLM) is an important brainstem region that regulates SNA to peripheral tissues. Brainstem oxidative stress and neuroinflammation are believed to be important contributors for augmented SNA in obesity. Our objective in this proposal is to determine the molecular mechanisms that are responsible for the initiation and sustenance of the pro-inflammatory milieu in the RVLM contributing to chronic increases in SNA in obesity. Our preliminary data suggests impaired Nrf2 signaling, a key regulator of antioxidant gene expression, along with premature cellular senescence, an irreversible growth arrest in cells as potential contributors to neuroinflammation in the RVLM in obesity. We will test the hypothesis that obesity causes Nrf2 dysfunction and promotes cellular senescence in the RVLM, which in turn contributes to neuroinflammation and increases in SNA. Guided by strong preliminary data, we will test this hypothesis in three aims. 1) Determine the contribution of Nrf2 dysfunction to oxidative stress in the RVLM and its impact on obesity-induced sympathoexcitation. Our working hypothesis, based on our preliminary data, is that obesity causes impairment in Nrf2 signaling in the RVLM leading to increase in oxidative stress and SNA in obesity. 2) Determine the role of senescent cells in RVLM in mediating neuroinflammation and sympathoexcitation in obesity. We postulate that activation of p16-dependent senescence program in the RVLM contributes to neuroinflammation and is responsible for increases in SNA in obesity. We predict that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means (senolytic drugs), will decrease neuroinflammation and SNA in obesity. 3) Determine the role of Nrf2 dysfunction in initiating the senescence program in the RVLM. Our working hypothesis, based on our preliminary data, is that chronic oxidative stress resulting from Nrf2 dysfunction induces premature senescence in the RVLM. Our work is innovative in that it will be the first to investigate cellular senescence in the brainstem as a mechanism for obesity-induced sympathoexcitation. We will utilize novel transgenic mouse models and state-of-the-art techniques including direct nerve recordings and mouse telemetry system to measure SNA and cardiovascular functions, respectively. We expect that the proposed studies will break new ground in the development of novel interventions against obesity-related cardiovascular risk. In addition, the proposed research will significantly enhance the research environment at Oklahoma State University and offer excellent training opportunities for graduate and undergraduate students in cutting-edge cardiovascular research.

肥胖是心血管疾病（包括高血压）的主要危险因素， 机制尚不清楚。越来越多的证据表明，交感神经活动（SNA） 在肥胖性高血压的病理生理学中起着至关重要的作用。延髓头端腹外侧 （RVLM）是调节SNA向外周组织的重要脑干区域。脑干氧化应激 和神经炎症被认为是肥胖症SNA增强的重要贡献者。我们的目标 在这个建议中，是确定负责引发的分子机制， RVLM中促炎环境的维持有助于肥胖患者SNA的慢性增加。我们 初步数据表明，受损的Nrf 2信号传导，抗氧化基因表达的关键调节因子，沿着 过早的细胞衰老，细胞中不可逆的生长停滞，作为 肥胖症患者RVLM中的神经炎症。我们将检验肥胖导致Nrf 2功能障碍的假设， 并促进RVLM中的细胞衰老，这反过来又有助于神经炎症并增加 在SNA中。在强有力的初步数据的指导下，我们将在三个目标中检验这一假设。1)确定 Nrf 2功能障碍对RVLM中氧化应激的贡献及其对肥胖诱导的 交感神经兴奋我们的工作假设，基于我们的初步数据，是肥胖导致损害 RVLM中的Nrf 2信号传导导致肥胖症中氧化应激和SNA的增加。2)确定角色 RVLM中衰老细胞在肥胖中介导神经炎症和交感神经兴奋中的作用。我们推测 RVLM中p16依赖性衰老程序的激活有助于神经炎症， 导致SNA在肥胖症中的增加。我们预测，衰老细胞的消除，无论是通过 遗传操作（p16- 3 MR小鼠模型）或通过药理学手段（衰老清除药物）， 神经炎症和SNA在肥胖中的作用。3)确定Nrf 2功能障碍在启动衰老中的作用 RVLM中的程序。我们的工作假设，基于我们的初步数据，是慢性氧化应激， 由Nrf 2功能障碍引起的衰老诱导RVLM的过早衰老。我们的工作是创新的， 将是第一个研究脑干细胞衰老作为肥胖诱导的一种机制， 交感神经兴奋我们将利用新的转基因小鼠模型和最先进的技术，包括 直接神经记录和鼠标遥测系统来测量SNA和心血管功能， 分别我们期望这些研究能为小说的发展开辟新的天地 干预肥胖相关的心血管风险。此外，拟议的研究将大大 改善俄克拉荷马州州立大学的研究环境，并提供良好的培训机会， 研究生和本科生在尖端的心血管研究。