Advancing the health and well-being of animals and people


Fellow: Colin Young

Mentor: Robin Davisson
Contact Information: Email: cny2@cornell.edu; Phone: 607-253-3677
Sponsor: American Physiological Society
Grant Number: N/A
Title: Dissecting the Role of Endoplasmic Reticulum Stress and NKFB Activation in Neurogenic Hypertension
Annual Direct Cost: $81,000
Project Period: 07/01/11-06/30/13

DESCRIPTION (provided by applicant): An estimated one billion people worldwide are hypertensive, with greater than 90% of reported cases being classified as idiopathic hypertension (i.e., no identifiable cause). While a multitude of factors have been implicated in the pathogenesis of hypertension, neuro-cardiovascular dysfunction due to inappropriate angiotensin II (Ang II) signaling within the brain has emerged as a key mechanism. Indeed, chronic systemic infusion of low dose Ang II (“slow pressor”) in mice, a well-established model which closely mimics the development of human hypertension, is associated with alterations in CNS neuronal gene expression. Previous findings from our laboratory have demonstrated that reactive oxygen species (ROS) within the subfornical organ (SFO), a circumventricular forebrain region lacking a blood brain barrier, are crucial in driving Ang II mediated neurohumoral dysfunction. However, the downstream molecular effectors of Ang II-induced ROS in CNS cardiovascular neurons are not defined. Using an approach that combines highly selective genomic interventions and integrative cardiovascular physiological analysis in mice, we will test the overall hypothesis that endoplasmic reticulum stressmediated activation of nuclear factor κB in the SFO of the brain mediates neurogenic hypertension induced by slow pressor Ang II infusion. Endoplasmic reticulum stress (ER stress) has recently emerged as a pathophysiological cause of numerous diseases; however a role for ER stress in mediating hypertension remains unknown. Thus, in Specific Aim 1 we will focus on the link between Ang II/ROS signaling and ER stress in the SFO. In Specific Aim 2 we will investigate a role for the transcription factor nuclear factor κB (NFκB) in the SFO in mediating neurogenic hypertension. Although NFκB is a crucial transcription factor known to modulate signaling cascades in response to oxidative stress, relatively little is known about Ang II/ROS mediated activation of NFκB in central cardiovasculatory regions, such as the SFO. Finally, based on evidence that ER stress pathways intersect directly with NF?B activation, in Specific Aim 3 we will examine a functional link between ER stress and NFκB in the SFO in mediating slow pressor Ang II hypertension. A combination of genomic interventions (viral gene transfer, genetically engineered animals) and integrative cardiovascular physiological analysis in the mouse will be used to begin to understand, for the first time, endoplasmic reticulum biology and transcriptional regulation in neuro-cardiovascular control. Overall, the findings from these studies will significantly advance our understanding of the underlying molecular mechanisms driving neurogenic hypertension, and may provide novel therapeutic target(s) for the treatment of hypertensive disease states. In addition, this project provides a critical training opportunity for Dr. Colin Young in physiologicalgenomic analysis of cardiovascular function and disease, which will compliment his graduate training in human neuro-cardiovascular physiology.