Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem

项目总结/摘要 高血压影响近一半的人口，是心脏病发作和中风的主要危险因素， 是美国第一和第三大死因 肾素-血管紧张素系统（RAS）是研究最多的血压控制机制之一。的 RAS的经典观点涉及底物血管紧张素原的顺序切割，导致 循环血管紧张素II（ANG）升高。除了在流通中作为一个经典的 （内分泌）激素系统，包括大脑在内的几个组织产生局部作用的ANG，支持 RAS的自分泌/旁分泌/内分泌形式在这些组织内局部起作用的概念。 然而，这一科学前提受到了挑战，由于难以检测肾外组织中的肾素， 机关事实上，催化水解除去前片段的酶，这是蛋白质合成所需的。 在肾外组织中不存在肾素的活化。利用上级的分子技术， 特异性和敏感性，我们能够识别特定的细胞位于头端腹外侧延髓（RVLM） 表达肾素。我们还观察到，在神经源性高血压模型中，如缺乏 替代性肾素亚型（renin-b），经典的肾素亚型（renin-a）编码 RVLM内的前原肾素。这些数据一直是我们询问肾素功能的驱动力- RVLM内的ANG表达细胞，此外，这些细胞是否在区域内启动ANG信号传导 邻近RVLM通过分泌前肾素到富含血管紧张素原的细胞外间隙？一 回答这些问题的关键一步是破译前肾素是如何被激活的。前肾素受体的发现 (PRR)，一种结合前肾素并诱导其活化而不裂解前片段的受体，可能 成为解决这个问题的关键人物。近年来，几种非ANG依赖性和（前）非肾素依赖性 PRR的功能已得到证实。从那时起，PRR介导RAS局部激活的作用 已经受到质疑鉴于这一领域长期存在的争议，我们的基本目标是澄清 PRR在RVLM内的生理和分子作用，然后分离依赖于PRR的作用。 RAS与独立于ANG生成的RAS相比。最后，我们提出了一个转录组学 方法来确定神经元和分子签名的肾素表达细胞内RVLM。 总的来说，该项目将促进对这些人的持续技术、知识和专业培训。 候选人，并协助建立一个独立的研究实验室，在学术研究 机构。

PROJECT SUMMARY/ABSTRACT Hypertension affects nearly half of the population and it is the principal risk factor for heart attack and stroke, the leading first and third cause of death in the United States. The renin-angiotensin system (RAS), is one of the most studied mechanisms of blood pressure control. The classical view of the RAS involves a sequential cleavage of the substrate angiotensinogen resulting in the elevation of circulating angiotensin II (ANG). In addition to functioning within the circulation as a classical (endocrine) hormone system, several tissues including the brain produce local acting ANG, supporting the concept that autocrine/paracrine/intracrine versions of the RAS act locally within these tissues. However, this scientific premise has been challenged due to the difficulties to detect renin in extrarenal organs. Indeed, the enzymes catalyzing the hydrolytic removal of the prosegment, which is required for the activation of renin, are absent in extrarenal tissues. Utilizing cutting edge molecular techniques with superior specificity and sensitivity we were able to identify specific cells located in the rostral ventrolateral medulla (RVLM) that express renin. We also observed that in a model of neurogenic hypertension, such as mice lacking the alternative renin isoform (renin-b), there is a disinhibition of the classical renin isoform (renin-a) encoding preprorenin within the RVLM. This data has been our driving force to interrogate what is the function of renin- expressing cells within the RVLM, and moreover, are these cells initiating ANG signaling within the areas adjacent to the RVLM by secreting prorenin to the extracellular space which is abundant of angiotensinogen? A key step to answer these questions is to decipher how prorenin is activated. The discovery of prorenin receptor (PRR), a receptor that binds prorenin and induces its activation without the cleavage of the prosegment, might be a key player to solve this problem. In the recent years, several ANG-independent and (pro)renin-independent functions of PRR have been demonstrated. Since then, the role of PRR mediating the local activation of the RAS has been questioned. Given the long-held controversy in this field, our fundamental goal is to clarify the physiological and molecular role of PRR within the RVLM and then to dissociate the actions that are dependent of the RAS versus those that are independent of the generation of ANG. Finally, we propose a transcriptomic approach to identify the neuronal and molecular signature of the renin-expressing cells within the RVLM. Collectively, this project will facilitate continued technical, intellectual, and professional training for the candidate, and assist in the establishment of an independent research laboratory at an academic research institution.