Our proposal seeks to understand the adaptive response of the brain to blood pressure inputs, and in particular the role of Angiotensin II (Angll) in this response. We will focus on the nucleus tractus solitarius (NTS) which plays a key role in the central regulation of cardiovascular performance, and on the Ang II AT1 receptor (AT1R) which acts within the brain to increase sympathetic outflow and blood pressure, effects which play a major role in hypertension. The central control function is highly adaptive, for example to Ang II, and also in response to sustained changes in blood pressure inputs. These processes alter the cellular state and future input-output neuronal responses via intracellular signaling mechanisms that have intermediate- and long-time scale influences on membrane electrical behavior and neurotransmitter outputs. In the present study, we will study these adaptive processes regulation using the AT1 receptor and acute hypertension as disturbances to activate NTS adaptive processes. Although the physiology of the NTS Ang II system in hypertension is well established, the cellular and molecular basis of central control hyperactivity is not understood. It is clear that it is a complex, multifactorial process involving AT1R initiated signaling processes and transcriptional regulatory network activities that alters the state of NTS and its output neuroelectrophysiology. The approach of the present proposal involves examining these processes together as a single cellular system. The behavior of this complex system involves dynamic interactions that are difficult to predict using qualitative reasoning and there is a need for experimentally validated computational modeling approaches at the systems level. These approaches will be invaluable in generation of hypotheses and will provide a framework for the systematic comparison of data collected across experiments. In order to study these processes the present project proposes three specific Aims:
Aim 1 models the influences of AT1R on gene regulation and the multi-level signaling-nucleus loop that produce changes in gene and protein expression and enzyme activities. The approach of the aim is to develop mathematical models suitable for in silico simulation study, and to refine these models iteratively by a process of testing predictions experimentally.
Aim 2 models the role of the AT1R activated adaptive processes from Aim 1 in the NTS response to AT1R in acute hypertension over the initial time course of neuronal adaptation. The approach is to make specific predictions as to TF and signaling activities involved in this role, and to test these predictions experimentally, improving the model and revealing key activities involved in the process.
Aim 3 models the AT1R influences on membrane channel kinetics resulting in modified firing behavior, and the effects of altered gene expression in response to AT1R activation on this system and behavior. The approach is to test these predictions at the level of effects on molecular processes involved in the physiological response, including feedback from gene regulatory responses. ? ? ? ? ? ? ? ?
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