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Discovery Studies to Identify Novel Regulators of Lysosome Biogenesis in C. elegans

- TFEB (HLH-30) independent pathways of lysosome biogenesis: We have chosen to study a C. elegans model system to uncover physiologic role of TFEB (and iother MiT/TFE pathway transcription factors, namely TFE3 and MiTF) as there is only one ortholog for all three of these transcription factors in the worm, namely hlh-30. In recently published studies (Murphy et al. PLOS Biology 2019), we have described a critical role for this pathway in driving transcription of the TOR machinery, which is critical for sustaining survival with refeeding after starvation. We have discovered an alternate pathway for lysosome biogenesis that bypasses HLH-30, via linoleic acid-driven activation of NHR-31. In ongoing work, we are examining evolutionarily conserved pathways in mammals to determine if their activation will be sufficient to drive lysosome biogenesis in scenarios where TFEB activity is suppressed (as in cardiomyopathy; Ma et al JAHA 2019) and beta cells in diabetes (Liu et al. Autophagy 2017). We have also set up genetic screens to discover alternate pathways for lysosome biogenesis in this model system.


- HLH-30 dependent pathways in innate immune response: In recently published studies (Kumar et al. Dev Cell 2019), we have collaborated with Kerry Kornfeld to describe a critical role for HLH-30 in the immune response to infection in worms. This function mirrors the previously described critical role for TFEB and TFE3 in macrophage response to LPS. This work also complements our ongoing studies in mammalian tissues with myeloid-specific targeting of TFEB and TFE3 to determine their role in engendering the immune response in the setting of myocardial infarction. In ongoing work, we are evaluating if bypassing the TFEB/TFE3 pathways based upon our worm studies will have a protective effect in the setting of sterile inflammation in the setting of MI.


- Role of lysosomes in handling toxic metals: In collaborative work with Dr. Kerry Kornfeld (whose lab has an interest in understanding mechanisms for zinc homeostasis), we have become interested in understanding how lysosomes handle and store toxic metals. In ongoing work which we are seeking funding support for, we are examining the hypothesis that stimulating lysosome biogenesis will increase their ability to take up and store toxic metals and prevent heavy metal toxicity. This work will be potentially high impact given the issues with environmental toxicity with lead and cadmium that has come to the forefront in many communities in the US.