The Neuro-Immuno Axis in a Genetic Model of Hypertension

描述（由申请人提供）：本申请描述了一个研究培训项目，旨在提高申请人的技能，使其能够在分子和细胞水平上独立从事心血管疾病神经免疫机制的研究。研究支持部分将研究神经免疫相互作用在原发性高血压发展和维持中的分子和细胞机制。到2025年，估计全世界原发性高血压的发病率将达到15.6亿成年人。原发性高血压是导致死亡和心血管疾病的主要原因，因此引起了巨大的公共卫生关注。高血压是多种血管、神经和肾脏机制的结果。已知各种机制的潜在方面与炎症有关。然而，炎症与其他各种已知高血压机制的关系仍不清楚。新出现的数据表明自主神经系统及其神经递质激发和抑制先天和适应性炎症免疫反应的作用。初步结果表明，高血压先天炎症反应的胆碱能影响是异常促炎的，CD161a+先天免疫细胞群在原发性高血压遗传模型中异常存在。先天免疫细胞群可能在炎症机制中发挥作用，可能是高血压发展和维持的基础。目的1将定义CD161a+先天免疫细胞的免疫应答及其通过烟碱胆碱能（nAChR）和血管紧张素I型（AT1R）受体激活的调节。目的2将确定尼古丁胆碱能（nAChR）和血管紧张素1型（AT1R）受体调节SHR衍生免疫细胞群在体内高血压发展中的作用。总之，这些目标将阐明神经和免疫系统在高血压、终末器官损伤发展中的关系，并为未来解剖这种相互作用中涉及的信号机制奠定基础。建立明确的机制和识别特异性免疫细胞将有可能导致开发针对新分子靶点的治疗难治性原发性高血压的新药物。科学项目，配合职业发展计划，将提供获得额外技能的机会

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.