Role of LIN28B-mTOR axis in supporting cell plasticity and hair cell regeneration
Royal National Institute for Deaf People
Johns Hopkins University
The aim of the proposed study is to address whether re-activation of LIN28B-mTOR pathway allows for auditory hair cell regeneration in mammals. Loss of auditory hair cells due to disease or trauma is permanent and is the leading causes for hearing impairments and deafness in humans. Immature auditory supporting cells do regenerate hair cells in response to regenerative cues. However, such regenerative capacity sharply declines as supporting cells mature. We recently reported that the decline in supporting cell plasticity is linked to rising levels of let-7 miRNAs in supporting cells. The let-7 family of miRNAs are known inhibitors of cell proliferation, stemness and growth. Preliminary data suggest that overexpression of LIN28B, a mutual antagonist of let-7 miRNAs extends the window of supporting cell plasticity beyond the neonatal stage. Furthermore, preliminary studies suggest that LIN28B-enabled hair cell regeneration requires mTOR signalling.   Based on these findings, we hypothesize that mature supporting cells fail to regenerate hair cells due to their inability to re-activate LIN28B-mTOR signaling. Furthermore, based on LIN28B’s positive role in cell reprogramming, we hypothesize that LIN28B-mTOR signaling facilitates hair cell regeneration by promoting supporting cell de-differentiation. Aim 1 will address whether LIN28B-mTOR activation in supporting cells induces a transitional progenitor-like state by examining LIN28B-mTOR induced changes in supporting cell-specific gene expression during hair cell regeneration. Aim 2 will examine whether the re-activation of LIN28B and or mTOR signalling enables mature supporting cells to proliferate and generate hair cells using a novel organoid culture system.
2.1 Biological and endogenous factors