Hypertension is a primary contributor to cardiovascular disease, which is the leading cause of mortality in America. Current medications for hypertension have proven to be insufficient in the management of the disease, as millions of patients retain uncontrolled high blood pressure1. With this, the elucidation of novel therapeutic targets is essential for the eventual complete treatment of this multidimensional disease. The immune system, particularly T-lymphocyte activation, contributes to the pathogenesis of hypertension by exacerbating a pro-inflammatory environment2-7. However, the extracellular stimuli and intracellular mechanisms regulating this process in T-lymphocytes remain unclear. Furthermore, mitochondrial produced superoxide (O2?-) has been elucidated as a key molecular intermediate in various cell types during hypertension . Our preliminary data suggest mitochondrial O2?- is increased in T-lymphocytes from 8-14 norepinephrine-driven hypertensive mice suggesting the immune system may additionally utilize this reactive molecule as a critical intracellular signaling intermediate. This project will investigate the influence of mitochondrial O2?- in T-lymphocytes during the pathogenesis of hypertension. Molecular sources of O2?- and the contribution of altered mitochondrial O2?- specifically in T- lymphocytes to hemodynamic parameters will be investigated during the mentored phase of this project. In this mentored phase, I will expand upon my extensive redox biology experience by learning techniques related to cardiovascular and molecular physiology such as cellular respiration measurements, radiotelemetry utilization, nerve recording, genetic animal manipulation, and an array of molecular biology assays. Concurrently, I will continue my professional development by serving on national committees, mentoring junior trainees, participating in journal clubs, seminars, and coursework, manuscript writing and reviewing, and having semiannual evaluations by a trainee advisory committee. The independent phase of this project will allow me to establish myself in the field of cardiovascular physiology where I will continue investigations in T- lymphocytes during hypertension by examining how mitochondrial O2?- modulates nuclear gene signaling, regulation, and epigenetic landscapes specifically of the negative T-lymphocyte regulatory gene PD-1. Collectively, this project will address specific training deficits needed to establish an independent cardiovascular research laboratory at an academic research institution by continued technical, intellectual, and professional training, while at the same time employing and enhancing my current expertise.
Hypertension is a major contributor to cardiovascular disease, the number one killer in America, and our research is focused on understanding the underlying causes of this illness. Previous studies have discovered that molecules known as reactive oxygen species (ROS) are uncontrolled in hypertension in many cell types and that activation of immune system cells (i.e. T-lymphocytes) are essential in the propagation of the disease. In this project, we will investigate the influence of a specific ROS, mitochondrial superoxide (O2?-), on the activation and function of T-lymphocytes during the pathogenesis of hypertension. Understanding how ROS function in T-lymphocytes in a hypertensive state may lead to advances in the development of novel therapies designed to specifically target the ROS or ROS-induced molecular signatures in these immune cells.
| Case, Adam J; Roessner, Colton T; Tian, Jun et al. (2016) Mitochondrial Superoxide Signaling Contributes to Norepinephrine-Mediated T-Lymphocyte Cytokine Profiles. PLoS One 11:e0164609 |
| Wang, Hanjun; Case, Adam J; Wang, Wei-Zhong et al. (2016) Redox Signaling and Neural Control of Cardiovascular Function. Oxid Med Cell Longev 2016:7086018 |
| Case, Adam J; Zimmerman, Matthew C (2016) Sympathetic-mediated activation versus suppression of the immune system: consequences for hypertension. J Physiol 594:527-36 |
| Case, Adam J; Zimmerman, Matthew C (2015) Redox-regulated suppression of splenic T-lymphocyte activation in a model of sympathoexcitation. Hypertension 65:916-23 |
