Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Patricia J. Sime
Abstract
Herein, we provide evidence for cellular metabolic reprogramming as a driver of radiation-induced pulmonary fibrosis (RIPF). We are the first to identify a distinct metabolic signature for RIPF in a cohort of patients with radiographic sequela. We also used a RIPF mouse model to detect the metabolic pathways that enrich during pathogenesis. Our previous work highlighted the importance of lactate, a derivative of the glycolysis end-product pyruvate. Consequently, we took a special interest in the effects of radiation on the glycolysis pathway. We learned that radiation accelerates and reprograms glycolysis to an anabolic state in a pyruvate kinase M2 (PKM2)-dependent manner. Inhibition or tetramerization of PKM2 both with drug or siRNA knockdown blocks radiation-induced myofibroblast differentiation and lactate production. Radiation also increases the pentose phosphate pathway (PPP). When we inhibited the activity of a key PPP rate-limiting enzyme, glucose-6-phosphate dehydrogenase, with a drug, there was markedly reduced extracellular lactate, myofibroblast differentiation, and ECM deposition. We hypothesize that these PPP metabolites, i.e. ribose, spill over into glycolysis to compensate for glucose loss and contribute carbons for energy and lactate production. We propose that inhibition of the PPP overflow mode is a potential therapeutic target for RIPF. Future experiments will help to elucidate this hypothesis. Taken together, we propose that cellular metabolism is a viable therapeutic target for RIPF warranting further investigation. Although our preliminary RIPF patient study included 40% of Black participants, we wanted to improve the participation of historically underrepresented populations in our future studies. We focused on strategies needed to strengthen the relationship between cancer biologists, the Office of Community Outreach and Engagement (COE) at the Virginia Commonwealth University (VCU) Massey Comprehensive Cancer (MCC) Center, and the neighboring communities it serves. The office of COE has a COE champion program comprised of cancer biologists interested in COE who liaise with their fellow colleagues in COE and bridge basic science with the neighboring community. We worked with this program and existing community partnerships to conduct a community-based participatory research project. We took a special focus on the clinical trial participation barriers of rural geography and race by working with Brunswick County (rural population) and Petersburg County (majority Black population). We identified several themes from the scientist or lay perspective to highlight key areas that weaken community-scientist partnerships. We also provide evidence-based recommendations to basic science researchers to better engage and communicate with non-scientist audiences. These overall findings advance our knowledge of the mechanistic role of cellular metabolism in pulmonary fibrosis (PF), provide a novel therapeutic target for PF, and meaningful approaches to strengthen scientist-community partnerships.
Rights
© Josly Pierre-Louis Odoom
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-12-2024
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Chemical and Pharmacologic Phenomena Commons, Other Social and Behavioral Sciences Commons
