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

描述（由申请人提供）：肥胖是一个主要的全球健康问题，与高血压的发展直接相关。尽管许多因素可能起作用，但来自人类和动物模型的越来越多的证据表明，过度的中枢交感神经活动（SNA）在肥胖相关性高血压中起致病作用。然而，细胞应激源（如营养过剩）转化为交感神经过度活跃和动脉血压持续升高的机制尚不清楚。一种潜在的方法是通过激活可诱导的转录因子，包括核因子κ B (NF?B)，引起中枢神经系统（CNS）心血管神经元基因表达的长期变化。在这方面，越来越多的证据表明，血管紧张素能信号和脑内质网应激（ER应激）是饮食性肥胖（DIO）的关键机制；然而，下游分子效应尚不清楚。我们的主要初步研究结果表明，高血压是由血管紧张素能和内质网应激介导的中枢神经系统机制介导的。我们还提供了令人兴奋的初步证据，表明小鼠高脂肪饮食（HFD）喂养可诱导内质网应激和NF？关键中枢神经系统神经心脏调节区域的B激活，包括皮质下器官（SFO）和下丘脑室旁核（PVN）。采用基因组干预、创新成像技术和综合心血管生理分析相结合的方法，我们将在小鼠中验证Ang-II诱导内质网应激介导的NF？SFO-PVN轴上的B介导DIO所致的神经源性高血压。在具体目标1中，我们将全面分析NF？高脂饮食（HFD）喂养小鼠SFO-PVN轴的B。我们将进一步研究ang - ii介导的机制在NF驱动中的作用。在dio诱导的高血压发展过程中B的激活。有证据表明内质网应激通路与NF直接相交？B活化，在特异性靶2中，我们将研究内质网应激在介导NF？HFD期间SFO和PVN中B的激活。最后，在具体目标3中，在本提案的独立部分，私家侦探Colin Young博士将研究NF的功能作用。SFO-PVN轴中的B介导DIO交感神经过度活跃和高血压。这些研究与肥胖引起的高血压的设置有直接的翻译相关性，并且在逻辑上建立在PI在人类心血管生理学和交感神经记录方面的背景之上。此外，这些研究结果有可能显著推进我们对DIO神经源性高血压的潜在分子机制的理解，并可能为高血压疾病状态的治疗提供新的治疗靶点。此外，这些研究有可能建立和推进一个新的研究领域，同时为PI提供强大的培训和未来的研究框架。PI在人类神经心血管调节方面受过广泛的培训，目前正在获得应用基因组工具研究高血压小鼠模型中分子整合心血管/自主神经功能的知识和技能。因此，本提案的指导部分（目标1和2）将独特地定位PI在基础分子和综合人类转化研究的十字路口进行未来的独立调查（目标3）。在过去的十年里，Robin Davisson博士的实验室一直处于神经调节和高血压研究的前沿，是PI进行额外指导培训和执行拟议研究的首选场所。除了在基因组学，分子生物学和全动物心血管和自主生理学方面的高级培训外，戴维森博士和康奈尔大学的指导指导为职业发展和负责任的研究行为培训提供了极好的机会。除了保持强大的研究重点外，PI还将在实验室和机构层面寻求一些令人兴奋的机会，以提高他作为独立科学家的成熟度；包括进一步发展领导才能、提升教学技巧和辅导学员。总的来说，这个新颖而令人兴奋的提议有可能为PI的下一个独立阶段奠定坚实的基础。

DESCRIPTION (provided by applicant): 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 (NF?B). 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 NF?B 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 NF?B in the SFO-PVN axis mediates neurogenic hypertension induced by DIO. In Specific Aim 1 we will comprehensively profile NF?B 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 NF?B activation during the development of DIO-induced hypertension. Based on evidence that ER stress pathways intersect directly with NF?B activation, in Specific Aim 2, we will examine a role for ER stress in mediating NF?B 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 NF?B 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.