Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY/ABSTRACT Chronic limb threatening ischemia (CLTI) is the most severe form of peripheral artery disease (PAD). Endovascular or open revascularization procedures are the primary treatment options for patients with CLTI, however many patients that undergo surgical interventions still require limb amputation within 1-2 years. Recent discoveries have uncovered a CLTI-specific mitochondrial myopathy phenotype that is characterized by decreased mitochondrial respiration and oxidative phosphorylation, an altered mitochondrial proteome, and a deficient mitochondrial transcriptome that develops after surgical intervention. Analysis of control, mild PAD, and CLTI patient muscle specimens uncovered high abundance of pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression in CLTI muscle specimens. PDK4 phosphorylates the pyruvate dehydrogenase complex (PDH) to decrease its enzymatic activity. PDK4 is also elevated in other myopathic conditions and chronic activation of PDK4 has been linked to mitochondrial dysfunction and muscle atrophy, two prominent phenotypes observed in PAD/CLTI. Based on these observations, I hypothesize that PDK4 plays a casual role in the ischemic mitochondrial myopathy of CLTI. To test this hypothesis, I will first determine if ectopic expression of Pdk4 in the skeletal muscle of C57BL6 mice subjected to hindlimb ischemia (HLI) worsens the ischemic myopathy. This rodent model is known to be resistant to ischemic myopathy and mitochondrial dysfunction. Next, I will determine if PDH phosphorylation is necessary for the development of ischemic mitochondrial myopathy in CLTI. To accomplish this, I will use muscle-specific adeno-associated viruses to knockdown Pdk4 and overexpress pyruvate dehydrogenase phosphatase 1 (Pdp1), which reverses the PDH phosphorylation, in BALB/cJ mice subjected to HLI. If my hypothesis is correct, these experiments will establish PDK4 and PDH phosphorylation as a mechanistic driver of ischemic mitochondrial myopathy in CLTI and provide support for developing therapies that aim to reverse this event, including translational experiments with PDK4 inhibitors. More importantly, these studies will provide me extensive training in molecular biology, genetics, and mitochondrial biology which will enhance my abilities as a scientist to facilitate my transition to an independent position as a principal investigator in academia.
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