Rejuvenation of aged muscle stem cells and tissues
Sarcopenia, aging, and muscle regeneration
During aging, skeletal muscles undergo structural and functional alterations as a result of multiple dysregulated pathways. Our goal is to elucidate novel causal mechanisms of sarcopenia and use this knowledge to improve aged muscle function. Our preliminary data revealed a reduction in specific prostaglandins in aged muscles. We recently discovered that this reduction results from catabolism by 15-PGDH, the prostaglandin degrading enzyme. Overexpression of 15-PGDH in young muscles reduces PGE2 and PGD2 levels. These animals also experience an unexpectedly marked decrease in muscle mass and function, mimicking sarcopenia. We hypothesize that during aging, senescent and inflammatory cells accumulate in the muscle microenvironment and express 15-PGDH, which degrades PGE2 and PGD2, and causes muscle wasting, and that inhibition of 15-PGDH in aged muscles will increase PGE2 and PGD2 lipid metabolites and augment muscle mass and strength.
15-PGDH pharmacological inhibition improves aged muscle function
By employing new and novel whole genome next-generation sequencing and computational methodologies to map chromatin accessibility, DNA methylation, transcription factor binding and histone modifications, our lab seeks to reveal epigenetic mechanisms that control muscle stem cell identity, epigenetic memory, and muscle tissue homeostasis.
PGE2 treatment overcomes intrinsic defects in aged MuSC chromatin accessibility
Spinal Muscular Atrophy
Gene therapy has shown remarkable promise for the successful treatment of the root cause of spinal muscular atrophy (SMA). However, combined therapeutic approaches that treat all aspects of SMA, including regenerating muscle, are still urgently needed. We believe that our advances in aging-related muscle wasting and muscular dystrophy can be translated to SMA. We are testing if our novel muscle strengthening therapy, 15-PGDH inhibition, will synergize with an available therapy that restores SMN expression (the root cause of SMA) to increase neuromuscular junctions and improve muscle function and in a severe SMA mouse model. We hypothesize that increasing muscle strength after partial restoration of SMN will provide significant long-term benefits that will improve SMA patient quality of life.
SMN restoring therapy with 15-PGDH inhibition to improve motor function in a SMA mouse
Ventilator Induced Diaphragm Dysfunction and COVID-19
COVID-19 symptom severity is directly linked to age as well as other comorbidities such as diabetes, poor respiratory function, and cardiovascular disease. Many COVID-19 patients require respiratory support from a ventilator. Although many patients survive COVID-19, recovery is prolonged as a consequence of diaphragm muscle weakness and some never completely recover due to ventilator-induced diaphragm dysfunction (VIDD), a condition that reduces the ability of a patient to be weaned to independent breathing. There is currently no treatment for VIDD. This project proposes to acquire preclinical data in support of a therapy for VIDD. Our preliminary data suggest that Prostaglandin E2 , the target of our drug, acts on both muscle stem cells to augment their proliferation and regenerative function, and on mature myofibers to improve strength. Our drug, if proven effective, may allow earlier weaning from ventilators of COVID-19 patients and significantly improve COVID-19 outcomes.
Young vs Aged gene expression for 15-PGDH (HPGD)