The Neuro-Immuno Axis in a Genetic Model of Hypertension

描述(由申请者提供)：本申请描述了一项旨在提高申请者技能的研究培训计划，该计划将允许在分子和细胞水平上独立研究心血管疾病的神经免疫机制。研究支持部分将研究神经免疫相互作用在高血压的发展和维持中的分子和细胞机制。到2025年，全世界高血压的发病率估计将达到15.6亿成年人。高血压是导致死亡和心血管疾病的主要原因，因此是一个巨大的公共卫生问题。高血压是多种血管、神经和肾脏机制的结果。众所周知，各种机制的一个潜在方面涉及炎症。然而，炎症与高血压的其他各种已知机制之间的关系仍不清楚。新出现的数据表明，自主神经系统及其神经递质在激发和抑制先天和适应性炎症免疫反应方面发挥了作用。初步结果表明，高血压先天炎症反应的胆碱能影响是异常的促炎作用，在高血压的遗传模型中，CD161a+的先天免疫细胞群异常存在。可能在炎症机制中发挥作用的先天免疫细胞群可能是高血压发生和维持的基础。目的研究CD161a+天然免疫细胞的免疫应答及其通过激活烟碱型胆碱能(NAChR)和血管紧张素I型受体(AT1R)的调节作用。目的研究SHR来源免疫细胞的烟碱胆碱能(NAChR)和血管紧张素受体1型(AT1R)受体调控在体内高血压发病中的作用。总之，这些目标将阐明神经和免疫系统在高血压和终末器官损伤发展中的关系，并为未来剖析参与这种相互作用的信号机制奠定基础。建立明确的机制和识别特定的免疫细胞将有可能导致以新的分子靶点为靶点的新型治疗剂的开发，用于治疗药物难治性高血压。科学计划与职业发展计划相结合，将提供获得更多技能的机会。 作为一名成功的内科科学家，独立的职业生涯所需要的。

DESCRIPTION (provided by applicant): This application describes a program of research training to enhance the applicant's skills that will permit an independent career in investigation of neuro-immuno mechanisms in cardiovascular disease at the molecular and cellular level. The research support component will investigate molecular and cellular mechanisms of neuro-immunune interaction in the development and maintenance of essential hypertension. By the year 2025, the incidence of essential hypertension is estimated to reach 1.56 billion adults worldwide. Essential hypertension is a leading cause of mortality and cardiovascular disease, thus presenting an enormous public health concern. Hypertension is the consequence of multiple vascular, neural, and renal mechanisms. An under- lying aspect of the various mechanisms has been known to involve inflammation. However, the relationship of inflammation to the various other known mechanisms of hypertension remains unknown. Emerging data suggests a role for provocation and suppression of innate and adaptive inflammatory immune responses by the autonomic nervous system and its neurotransmitters. Preliminary results indicate that the cholinergic influence of the innate inflammatory response in hypertension is abnormally pro-inflammatory and that a CD161a+ innate immune cell population is abnormally present in a genetic model of essential hypertension. Innate immune cell populations that potentially play a role in the inflammatory mechanisms may underlie the development and maintenance of hypertension. Aim #1 will define the immune response of CD161a+ innate immune cells and its modulation by nicotinic cholinergic (nAChR) and angiotensin type I (AT1R) receptor activation. Aim #2 will determine the role of nicotinic cholinergic (nAChR) and angiotensin type 1 (AT1R) receptor modulation of SHR derived immune cell populations in the development of hypertension in vivo. Together these aims will elucidate the relationship between the nervous and immune systems in the development of hypertension, end-organ damage, and set the stage for future dissection of the signaling mechanisms involved in this interaction. Establishing definitive mechanisms and identifying specific immune cells will potentially lead to the development of novel therapeutic agents for the treatment of medically refractory essential hypertension, targeting novel molecular targets. The scientific program, in concert with the career development plan, will provide the opportunity to acquire additional skills needed for an independent career as a successful physician-scientist.