Role of Central Neural NFkB and ER Stress in Obesity-induced Hypertension

项目摘要 肥胖是一个主要的全球性健康问题，并与高血压的发展直接相关。虽然 许多因素可能起作用，从人类和动物模型中积累的证据表明， 过度的中枢交感神经活动（SNA）在肥胖相关的高血压中起致病作用。 然而，细胞应激源，如营养过剩，转化为交感神经系统的机制， 活动过度和动脉血压持续升高仍不清楚。一种可能的方法是 引起中枢神经系统（CNS）心血管神经元中基因表达的长期变化 通过激活可诱导的转录因子，包括核因子κ-B（NFκB）。在这 关于这一点，越来越多的证据表明，血管紧张素能信号和内质网应激（ER 脑内的应激）是饮食诱导肥胖（DIO）的关键机制;然而， 影响因素尚不清楚。我们的主要初步研究结果表明，DIO高血压是由 血管紧张素能和ER应激介导的CNS机制。我们还提供了令人振奋的初步证据 高脂饮食（HFD）喂养小鼠诱导ER应激和NFκB活化， 心脏调节区，包括穹窿下器（SFO）和室旁核 （PVN）。使用结合基因组干预、创新成像技术和 综合心血管生理分析在小鼠中，我们将测试的总体假设，血管生成素II， 内质网应激介导的NFκB在SFO-PVN轴中的活化介导神经源性高血压 由DIO引起。 在具体目标1中，我们将全面分析高脂饮食（HFD）期间SFO-PVN轴中的NFκB 喂养老鼠我们还将研究Ang-II介导的机制在驱动NFκB 在DIO诱导的高血压的发展过程中激活。基于ER应激通路 与NFκB活化直接相关，在具体目标2中，我们将研究ER应激在介导 HFD期间SFO和PVN中的NFκB活化。最后，在具体目标3中， 在该提案中，PI Colin Young博士将研究NFκB在SFO-PVN轴中的功能作用 介导DIO交感神经过度活跃和高血压。这些研究与翻译有着直接的关联， 肥胖引起的高血压的设置，并在逻辑上建立在PI的心血管背景 生理学和人类交感神经记录。此外，这些调查的结果 有可能显着推进我们对潜在的分子机制的理解， DIO神经源性高血压，并可能为高血压的治疗提供新的治疗靶点。 疾病状态。此外，这些研究有可能建立和推进一个新的领域， 研究，同时为PI提供强大的培训和未来的研究框架。的PI 在人类神经-心血管调节方面接受了广泛的培训，目前正在获得知识， 应用基因组工具研究分子整合的心血管/自主神经功能的技能， 小鼠高血压模型。因此，本提案的指导部分（目标1和2）将独特地 定位PI在基础分子和生物学的交叉点进行未来的独立研究（目标3）， 整合人类转化研究。 Robin Davisson博士的实验室是PI进行额外指导培训的首要场所 并执行拟议的研究，一直处于神经调节和高血压研究的前沿 在过去的十年里。除了在基因组学，分子生物学和整个动物的高级培训 心血管和自主神经生理学，戴维森博士和康奈尔大学的指导 为职业发展和负责任行为的培训提供极好的机会 研究。除了保持强大的研究重点外，PI还将追求一些令人兴奋的目标 在实验室和机构层面的机会，以提高他作为一个独立的科学家的成熟; 包括进一步发展领导素质，提高教学技能和指导 实习生总的来说，这一新颖而令人兴奋的提案有可能为下一个提案奠定坚实的基础。 PI的独立阶段。

PROJECT SUMMARY Obesity is a major global health concern and is directly linked to the development of hypertension. Although a number of factors may contribute, accumulating evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in obesity-associated hypertension. However, the mechanisms by which cellular stressors, such as nutritional excess, translate into sympathetic overactivity and sustained elevations in arterial blood pressure remain unclear. A potential means is by evoking long-term changes in gene expression in central nervous system (CNS) cardiovascular neurons through the activation of inducible transcription factors, including nuclear factor kappa-B (NFκB). In this regard, there is mounting evidence that angiotensinergic signaling and endoplasmic reticulum stress (ER stress) within the brain are key mechanisms in diet-induced obesity (DIO); however the downstream molecular effectors remain unclear. Our key preliminary findings show that DIO-hypertension is mediated by angiotensinergic and ER stress mediated CNS mechanisms. We also provide exciting preliminary evidence that high fat diet (HFD) feeding in mice induces ER stress and NFκB activation in critical CNS neuro- cardioregulatory areas, including the subfornical organ (SFO) and paraventricular nucleus of the hypothalamus (PVN). Using an approach that combines genomic interventions, innovative imaging techniques and integrative cardiovascular physiological analysis in mice, we will test the overall hypothesis that Ang-II- induced ER stress-mediated activation of NFκB in the SFO-PVN axis mediates neurogenic hypertension induced by DIO. In Specific Aim 1 we will comprehensively profile NFκB in the SFO-PVN axis during high fat diet (HFD) feeding in mice. We will additionally examine a role for Ang-II-mediated mechanisms in driving NFκB activation during the development of DIO-induced hypertension. Based on evidence that ER stress pathways intersect directly with NFκB activation, in Specific Aim 2, we will examine a role for ER stress in mediating NFκB activation in the SFO and PVN during HFD. Finally in Specific Aim 3, during the independent portion of this proposal, the PI, Dr. Colin Young, will examine a functional role for NFκB in the SFO-PVN axis in mediating DIO sympathetic overactivity and hypertension. These studies have direct translation relevance to the setting of obesity-induced hypertension and build logically upon the PI's background in cardiovascular physiology and sympathetic neural recordings in humans. Furthermore, the findings from these investigations have the potential to significantly advance our understanding of the underlying molecular mechanisms driving DIO neurogenic hypertension, and may provide novel therapeutic target(s) for the treatment of hypertensive disease states. In addition, these studies have the potential to establish and advance a novel area of research, while at the same time providing a strong training and future research framework for the PI. The PI has extensive training in human neuro-cardiovascular regulation and is currently acquiring the knowledge and skills for applying genomic tools to investigate molecular integrative cardiovascular/autonomic function in mouse models of hypertension. As such, the mentored portion of this proposal (Aims 1 and 2) will uniquely position the PI to pursue future independent investigations (Aim 3) at the crossroads of basic molecular and integrative human translational research. The laboratory of Dr. Robin Davisson is the premier venue for the PI to pursue additional mentored training and perform the proposed studies, having been at the forefront of neural regulation and hypertension research over the past decade. In addition to advanced training in genomics, molecular biology and whole animal cardiovascular and autonomic physiology, the mentored guidance of Dr. Davisson and Cornell University provide a superb opportunity for the progression of career development and training in the responsible conduct of research. In addition to maintaining a strong research focus, the PI will pursue a number of exciting opportunities at the laboratory and institutional level to enhance his maturation as an independent scientist; including further development of leadership qualities, advancement of teaching skills and mentoring of trainees. Overall, this novel and exciting proposal has the potential to lay a strong foundation for the next independent phase of the PI.