Thursday, May 9, 2024
5/9/2024
Project Abstract The heart is an obligate aerobic organ, making it one of the highest oxygen consumers of any organ in the body. Cardiac dependence on oxidative metabolism makes the heart particularly vulnerable to oxygen insufficiency, which is observed in many diseases including ischemic heart disease and heart failure, as well as pulmonary pathologies such as chronic obstructive pulmonary disease. These constitute the leading causes of morbidity and mortality in the world. The heart retains some ability to adapt to mild hypoxia, indicating that protective pathways exist that could be harnessed to improve cardiac function in patients with chronic hypoxia pathologies. Cardiomyocytes (CMs)—the parenchymal cell type of the heart—are metabolically flexible and can shift their fuel source preference in response to hypoxia. This plasticity suggests that interventions that rewire CM metabolic pathways can reduce tissue damage. However, our ability to design such interventions is currently limited by our understanding of the molecular mediators of these metabolic changes. This proposal aims to gain a systems-level understanding of the pathways that facilitate adaptive and maladaptive metabolic changes in CMs in response to hypoxia, with the long-term goal of targeting these pathways as novel therapeutics. To accomplish this, I have developed a functional genomics platform in iPSC-CMs. In a preliminary genome-wide CRISPRi survival screen in iPSC-CMs in chronic hypoxia, my initial findings paradoxically suggest that suppressing excessive accumulation of intracellular glucose may be protective in hypoxia. Interestingly, a related clinical phenomenon supports this general concept – hyperglycemia at the time of ICU admission has been shown to correlate with worse outcomes following MI or cardiac arrest, independent of diabetes status. These findings suggest that shifting fuel sources is a central component of the (mal)adaptive hypoxic response. I hypothesize that modulation of hypoxia-responsive fuel rewiring can serve as a therapeutic strategy to restore CM function during cardiac pathologies caused by oxygen deprivation. I will test this hypothesis through three separate aims. First, I will systematically identify the regulators of cardiomyocyte survival in pathological hypoxia using a functional genomics screen. By creating nutrient limiting conditions, I will determine the pathways that enable substrate switching in hypoxia. Second, I will determine the metabolic fates of glucose during CM hypoxia using isotope tracer studies. Third, I will target glucose uptake and processing pathways genetically to restore CM survival and electrophysiology during pathological hypoxia. These experiments will identify novel therapeutic targets related to fuel rewiring in CMs and will provide mechanistic insights into cardiac glucose toxicity to enable a further understanding of the pathophysiology of cardiac hypoxia.
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