Metabolite Transport Modulation to Mitigate Ischemic-Reperfusion Injury

Project Summary/Abstract This proposal investigates metabolite transport modulation in the setting of myocardial ischemic-reperfusion (I/R) injury. I/R is a consequence of the standard of care for heart attack patients and leads to heart failure (HF). The overall aim of this grant is to develop novel interventions to mitigate injury to the heart by focusing on metabolite transport modulation. The experiments focus on the inhibition of monocarboxylate transporter 4 (MCT4), which is crucial for lactate excretion, and potentially other metabolites from cardiomyocytes. My previous research has shown the potential for cardioprotection with MCT4 inhibition. The four specific aims that are proposed in this grant are as follows: K99-Aim 1: Define metabolite transport and utilization in response to I/R with and without MCT4 inhibition in vitro. K99-Aim 2: Determine metabolite transport in vivo during I/R injury with MCT4 inhibition. R00-Aim 1: Test whether MCT4 inhibition is sufficient to protect against development of ischemic cardiomyopathy. R00-Aim 2: Determine roles for MCT4 inhibition in preserving human myocardium in ex vivo injury models. By uncovering how MCT4 inhibition influences myocardial biology, my research offers a therapeutic approach to alleviate cardiac injury. Continued training will add new dimensions to my knowledge base that will be broadly applicable to my goal of leading a lab at a top-tier research institution studying protection from cardiovascular diseases (CVD). These avenues of research have the potential to alter our understanding and approaches to cardiovascular medicine, and my long-term vision is to develop novel approaches in the fight against CVD that will improve quality of life. To accomplish this, I have a team of supportive faculty mentors who are experts in cardiovascular and metabolism research. The UofU has exceptional researchers who collaborate through institutional organizations such as the Nora Eccles Harrison Cardiovascular Research & Training Institute and the Diabetes and Metabolism Research Center. This award is foundational for my scientific career, bridging in- depth research with practical, clinical utility in cardiovascular medicine. These experiments will lay the groundwork for new therapeutic approaches during cardiac injury. Under the guidance of my co-mentors and my team of collaborators during this K99/R00, this grant will allow me to eventually transition seamlessly from my current mentored position into an independent research group leader at an R1 institution.