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

肥胖是包括高血压在内的心血管疾病发展的主要危险因素，但 机制尚不清楚。越来越多的证据表明，交感神经活动(SNA)的增加 在肥胖性高血压的病理生理学中起着至关重要的作用。延髓吻侧腹外侧部 (RVLM)是一个重要的脑干区域，负责调节SNA对周围组织的影响。脑干氧化应激 神经炎症被认为是肥胖患者SNA增加的重要因素。我们的目标 在这项建议中是为了确定负责引发和 RVLM中促炎环境的维持有助于肥胖患者SNA的慢性增加。我们的 初步数据表明，Nrf2信号受损，Nrf2信号是抗氧化基因表达的关键调节因子， 细胞过早衰老是细胞中不可逆转的生长停滞，是导致 肥胖患者右室旁路神经炎性改变。我们将检验肥胖导致Nrf2功能障碍的假设 并促进RVLM中的细胞衰老，进而导致神经炎症和增加 在SNA中。在强劲的初步数据指导下，我们将从三个方面检验这一假说。1)确定 Nrf2功能障碍在RVLM氧化应激中的作用及其对肥胖的影响 交感神经兴奋。根据我们的初步数据，我们的工作假设是肥胖会导致损伤 在RVLM中的Nrf2信号导致肥胖时氧化应激和SNA的增加。2)确定角色 RVLM中衰老细胞在介导肥胖的神经炎症和交感兴奋中的作用。我们假设 RVLM中p16依赖的衰老程序的激活促进了神经炎症，并 这是肥胖人群SNA增加的原因。我们预测，通过以下方式消除衰老细胞 基因操作(p16-3mr小鼠模型)或通过药物手段(感觉性药物)将会减少 肥胖症的神经炎症和SNA。3)确定Nrf2功能障碍在启动衰老中的作用 RVLM中的程序。根据我们的初步数据，我们的工作假设是慢性氧化应激 Nrf2功能障碍导致RVLM早衰。我们的工作是创新的，因为它 将是第一个研究脑干细胞衰老作为肥胖诱导机制的人 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 直接神经记录和老鼠遥测系统来测量SNA和心血管功能， 分别进行了分析。我们期待拟议的研究将为小说的发展开辟新的天地 预防肥胖相关心血管风险的干预措施。此外，拟议的研究将显著 改善俄克拉荷马州立大学的研究环境，并为以下项目提供良好的培训机会 心血管尖端研究的研究生和本科生。

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.