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.
Essential hypertension is a leading cause of mortality and cardiovascular disease, thus presenting an enormous public health concern. To date, although it is clear that there are neural, renal and vascular components to the development and maintenance of hypertension, these alone or together do not account for the mortality. This proposal is designed to investigate the novel mechanisms involved in the interaction between the autonomic neurohormonal mediators and the immune system is abnormally pro-inflammatory in hypertension and leads to the development and maintenance of hypertension. The results of this proposal will help identify molecular and cellular targets for developing novel therapeutic treatments for essential hypertension.
|Harwani, Sailesh C; Ratcliff, Jason; Sutterwala, Fayyaz S et al. (2016) Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat. Circ Res 119:1101-1115|