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

描述(申请人提供)：肥胖是一个主要的全球健康问题，并与高血压的发展直接相关。虽然许多因素可能起作用，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动和动脉血压持续升高的机制仍不清楚。一种可能的方法是通过激活可诱导的转录因子，包括核因子-kappaB(NFkappaB)，来引起中枢神经系统(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，脑内的血管紧张素能信号和内质网应激(ER应激)是饮食诱导肥胖(DIO)的关键机制；然而，下游的分子效应尚不清楚。我们的主要初步发现表明，DIO-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，证明高脂饮食(HFD)在小鼠中诱导ER应激和关键的中枢神经-心脏调节区(包括穹隆下器官(SFO)和下丘脑室旁核(PVN))中的核因子？B激活。我们将采用基因组干预、创新的成像技术和综合心血管生理分析相结合的方法，检验Ang-II诱导的内质网应激介导的SFO-PVN轴的NF？B激活介导DIO诱导的神经原性高血压的总体假设。在特定的目标1中，我们将全面分析高脂饮食(HFD)喂养小鼠的SFO-PVN轴中的核因子？B。此外，我们还将研究血管紧张素转换酶II介导的机制在DIO诱导的高血压发展过程中驱动核因子B活化的作用。基于内质网应激途径与核因子B活化直接相交的证据，在特定的目标2中，我们将探讨内质网应激在HFD时SFO和PVN中介导核因子B活化的作用。最后，在具体目标3中，在本提案的独立部分，PI Colin Young博士将研究在SFO-PVN轴中NF？B在调节DIO交感神经过度活动和高血压中的功能作用。这些研究与肥胖性高血压的设定有直接的翻译相关性，并且从逻辑上建立在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提高我们对DIO神经源性高血压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(S)。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提供一个强有力的培训和未来的研究框架。PI在人类神经-心血管调节方面接受了广泛的培训，目前正在获得应用基因组工具在高血压小鼠模型中研究分子综合心血管/自主神经功能的知识和技能。因此，这项建议的指导部分(目标1和2)将独特地将PI定位为未来在基础分子和综合性人类翻译研究的十字路口进行独立研究(目标3)。Robin Davisson博士的实验室是PI进行额外指导培训和执行拟议研究的主要场所，在过去十年中一直处于神经调节和高血压研究的前沿。除了在基因组学、分子生物学和整个动物心血管和自主神经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。除了继续专注于研究工作外，创新进修学院亦会在实验室和院校层面寻求多项令人振奋的机会，以加强他作为独立科学家的成熟，包括进一步发展他的领导才能、提升教学技巧和辅导学员。总体而言，这一新颖而令人振奋的提议有可能为下一个独立阶段的和平倡议奠定坚实的基础。

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.