Recent evidence indicates that alterations in the neuronal control of blood pressure set point can cause hypertension, termed neurogenic hypertension. It is now plausible, and our hypothesis, that neurogenic hypertension is a major cause, a "missing link", in development of hypertension. Thus, understanding the molecular framework for neurogenic hypertension will facilitate development of improved treatment or cure of the disease, and predictive diagnostics. Our previous results focus the present proposal on the A2 catecholaminergic neurons in the nucleus tractus solitarius (NTS). The A2 neurons regulate blood pressure set point independent of any effect on baroreceptor reflex function or gain. A2 cells were also implicated by our transcript profiling studies of the molecular adaptive response of the NTS to hypertension, and by our gene regulatory network computational models of the NTS response. The present proposal will characterize the responses of A2 cells to acute sustained hypertension and use predictive modeling to understand the complex alterations in A2 cellular properties and molecular processes mediating their adaptive responses. We will also study the network behavior of the specific subsets of functionally connected A2 neurons related to blood pressure control. We will build and analyze detailed gene regulatory network models of functionally connected subsets of A2 neurons using an iterative experimental/computational biology approach. These network models will predict the adaptive mechanisms of A2 neurons underlying blood pressure set point control in particular in response to acute sustained hypertension. The predictions will be tested by in vivo genetic manipulation and molecular and physiological assays to reveal molecular interactions critical to maintaining normal blood pressure.
Essential hypertension is a major disease of unknown cause and continually increasing in prevalence. In this proposal, we seek to understand the response of neurons that affect blood pressure set point to acutely elevated blood pressure. By finding specific alterations in these neurons that underlie their adaptive processes, we aim to define mechanisms relevant to diagnostics and therapeutic approaches to hypertension.
|Park, James; Brureau, Anthony; Kernan, Kate et al. (2014) Inputs drive cell phenotype variability. Genome Res 24:930-41|