The Neuro-Immuno Axis in a Genetic Model of Hypertension

高血压遗传模型中的神经免疫轴

• 批准号: 9468391
• 负责人: Sailesh Harwani
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468391
• 关键词: Adrenergic Receptor; Adult; Age; Angiotensin Receptor; Angiotensins; Autonomic nervous system; Basic Science; Blood Vessels; Cardiovascular Diseases; Cells; Cellular biology; Cholinergic Receptors; Complement; Data; Development; Development Plans; Dissection; Dysautonomias; Essential Hypertension; Future; Genetic Models; Heart failure; Hematopoietic; Hypertension; Immune; Immune response; Immune system; Immunologics; Immunology; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Incidence; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-6; Investigation; Iowa; Kidney; Knowledge; Lead; Ligands; Maintenance; Mediating; Mediator of activation protein; Medical; Molecular; Molecular Target; Molecular and Cellular Biology; Nervous system structure; Neurotransmitters; Nicotine; Nicotinic Receptors; Organ; Physicians; Play; Population; Protein-Serine-Threonine Kinases; Protocols documentation; Public Health; Publishing; Receptor Activation; Receptor, Angiotensin, Type 1; Refractory; Research Personnel; Research Support; Research Training; Resources; Role; Scientist; Signal Transduction; Source; Splenocyte; Techniques; Therapeutic Agents; Training; Translational Research; Universities; alpha-bungarotoxin receptor; cardiovascular risk factor; career; career development; cellular targeting; cholinergic; cytokine; design; hypertensive heart disease; immunoregulation; in vivo; kidney vascular structure; mortality; novel; novel therapeutics; programs; public health relevance; receptor; relating to nervous system; response; skills

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.

描述（由申请人提供）：本申请描述了一项研究培训计划，以提高申请人的技能，该计划将允许在分子和细胞水平的心血管疾病中独立研究神经传染性机制。研究支持成分将研究神经免疫相互作用的分子和细胞机制，以发展和维持基本高血压。到2025年，据估计，基本高血压的发生率将达到全球15.6亿成人。基本高血压是死亡率和心血管疾病的主要原因，因此引起了巨大的公共健康问题。高血压是多种血管，神经和肾脏机制的结果。已知各种机制的一个不明智的方面涉及炎症。然而，炎症与高血压的各种其他已知机制的关系仍然未知。新兴数据表明，自主神经系统及其神经递质挑衅和抑制先天和适应性炎症免疫反应的作用。初步结果表明，先天性炎症反应在高血压中的胆碱能影响异常促炎，并且CD161A+先天免疫细胞群异常存在于基本高血压的遗传模型中。可能在炎症机制中发挥作用的先天免疫细胞种群可能是高血压发展和维持的基础。 AIM＃1将定义CD161A+先天免疫细胞的免疫反应及其对烟碱胆碱能（NACHR）和血管紧张素I型（AT1R）受体激活的调节。 AIM＃2将确定烟碱胆碱能（NACHR）和血管紧张素1型（AT1R）受体调节的SHR衍生免疫细胞群体在体内高血压发展中的作用。这些目的共同阐明了在高血压，最终器官损伤发展中神经和免疫系统之间的关系，并为将来解剖这种相互作用所涉及的信号传导机制奠定了基础。建立确定的机制并鉴定特定的免疫细胞可能会导致新型治疗剂的发展，以治疗医学上难治性的本质高血压，以靶向新的分子靶标。科学计划与职业发展计划一致，将为获得其他技能提供机会 作为成功的医师科学家独立职业所需的。