PROJECT SUMMARY/ABSTRACT
Pulmonary hypertension (PH) is a disease characterized by pulmonary vascular remodeling and poor gas
exchange, and eventually leads to right ventricular failure and death. Elevated heart and respiratory muscle
workloads contribute to diaphragm and cardiac impairments in PH; however, the physiological and molecular
bases are not fully understood. Vascular function is compromised in PH, resulting in an inability to match
oxygen delivery to demand, which is of increasing importance in the overworked diaphragm and heart.
However, the mechanisms underlying PH-induced vascular dysfunction and, arguably more important, targets
for mitigating such dysfunction remain unknown. Upregulation of reactive oxygen species and inflammatory
cytokines are thought to promote PH pathogenesis, which suggests that modulation of intracellular redox
pathways may serve as one potential mechanism responsible for the impaired vasomotor control with PH and
provides a potential therapeutic target to improve the compromised vascular function in PH.
Preliminary data supports that PH impairs endothelial-dependent and -independent vasorelaxation in
diaphragm arterioles, and therefore diaphragmatic blood flow. Importantly, endothelial-dependent and -
independent vasoreactivity may be improved by activation of the transcription factor, nuclear factor erythroid-
2–related factor 2 (Nrf2). However, the role of Nrf2 in improving coronary and diaphragm vascular function in
PH has never been determined. Therefore, our global hypothesis is that exercise training and
pharmacological Nrf2 activation will improve or restore coronary and diaphragm vascular function in
PH. Furthermore, we will assess the reliance upon Nrf2 for these adaptations in order to determine the
potential molecular basis for our findings.
This project will be completed at Kansas State University (KSU) under the guidance of Drs. David C. Poole
and Bradley J. Behnke. The training plan has been formulated to facilitate the development of technical
proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the
elements essential for the applicant to transition into an independent scientific career. The Poole and Behnke
Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich
scientific environment that will provide outstanding graduate training and research opportunities to gain new
insights into mechanisms of diaphragm blood flow regulation and vasomotor control in healthy and diseased
animal models.