The TSC/mTORC1 signaling axis is dysregulated in tuberous sclerosis complex (TSC). Everolimus, a rapamycin analog that partially inhibits mTORC1, is approved for the treatment of renal angiomyolipomas in TSC patients, but responses are not complete and regrowth begins after treatment discontinuation. microRNA (miRNA, miRs), which post-transcriptionally repress gene expression, have been shown to play a critical role in numerous disease processes; however, the role of miRNA in TSC and TSC therapeutic responses represents a key knowledge gap. In recently published work, we discovered a set of rapamycin-dependent miRNA, or Rapa-miRs. The unexpected finding that rapamycin upregulates pro-survival oncogenic miRNA, particularly miR-21, underlies our central hypothesis: inhibition of miRNA-dependent survival networks will enhance effectiveness of mTORC1 inhibition in angiomyolipoma therapy, leading to more complete and durable clinical responses. This hypothesis will be tested in three Specific Aims:
Aim 1 : To identify the regulatory mechanisms that lead to induction of miRNA by rapamycin.
Aim 2 : To identify biologically active rapamycin-dependent target genes of miR-21 in TSC2- deficient cells.
Aim 3 : To determine how the induction of miR-21 by rapamycin impacts the growth and survival of TSC2-deficient cells.
Our long-term goal is to elucidate the mechanisms through which rapamycin-induced microRNA impact the pathogenesis and treatment of renal disease in TSC. Multiple approaches for therapeutic targeting of miRs are under investigation, including antagomir strategies that have recently been found to be successful treating hepatitis and molecules such as genistein, which inhibits miR-21. Therefore, novel Rapa-miR focused strategies to enhance the magnitude and durability of response to mTOR inhibitors in TSC could have broad clinical impact in TSC and other diseases associated with mTOR activation.
| Ogórek, Barbara; Lam, Hilaire C; Khabibullin, Damir et al. (2018) TSC2 regulates microRNA biogenesis via mTORC1 and GSK3?. Hum Mol Genet 27:1654-1663 |
| Lam, Hilaire C; Liu, Heng-Jia; Baglini, Christian V et al. (2017) Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells. Oncotarget 8:64714-64727 |
