Department of Biomedical Sciences
Sponsor: American Heart Association - Founders Affiliate
Grant Number: 13POST14410020
Title: Dissecting the Role of Brain NFkB in Obesity-Induced Hypertension
Annual Direct Cost: $44,000
Project Period: 1/1/2013-12/31/2014
DESCRIPTION (provided by applicant): Obesity is a major global health concern and is directly linked to the development of hypertension. Although a number of factors may contribute, accumulating evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA) plays a role in obesity-associated hypertension. However, the mechanisms by which cellular stressors, such as nutritional excess, translate into sympathetic overactivity and sustained elevations in arterial blood pressure remain unclear. A potential means is by evoking long-term changes in gene expression in central nervous system (CNS) neurons through the activation of inducible transcription factors, including nuclear factor kappa-B (NFkB). In this regard, there is mounting evidence that angiotensinergic signaling and endoplasmic reticulum stress (ER stress) within the brain are key mechanisms in diet-induced obesity (DIO); however the downstream molecular effectors remain unclear. Our key preliminary findings show that DIO-hypertension is mediated by angiotensin-II (Ang-II) and ER stress-mediated CNS mechanisms. We also provide exciting preliminary evidence that high fat diet (HFD) feeding in mice induces ER stress and NFkB activation in critical CNS neuro-cardioregulatory nuclei, including the subfornical organ (SFO) and paraventricular nucleus (PVN) of the hypothalamus. Using an approach that combines genomic interventions, innovative imaging techniques and integrative cardiovascular physiological analysis in mice, we will test the overall hypothesis that Ang-II-induced ER stress-mediated activation of NFkB in the SFO-PVN axis mediates neurogenic hypertension induced by DIO. In Aim 1 we will comprehensively profile NFkB in the SFO-PVN axis during HFD feeding in mice. We will also examine a role for Ang-II-mediated mechanisms in driving NFkB activation during the development of DIO hypertension. Based on evidence that ER stress pathways intersect directly with NFkB activation, in Aim 2, we will examine a role for ER stress in mediating NFkB activation in the SFO and PVN during HFD. Finally in Aim 3, we will examine a functional role for NFkB in the SFO-PVN axis in mediating DIO sympathetic overactivity and hypertension. The findings from these studies have the potential to significantly advance our understanding of the underlying molecular mechanisms driving DIO neurogenic hypertension, and may provide novel therapeutic targets for the treatment of hypertensive disease states.