Identification of the molecular mechanisms preventing YAP-TEAD-mediated cell cycle re-entry in supporting cells of the mouse utricle

Project: Research project

Grant Program

Faculty Development Competitive Research Grants 2020-2022

Project Description

In vertebrates, the senses of hearing and balance rely on tiny patches of sensory epithelia consisting of mechanosensory hair cells intercalated by non-sensory supporting cells. While hair cells are solely responsible for conversion of mechanical stimuli into neural impulses, supporting cells can act as hair cell progenitors and regenerate hair cells after injury in all vertebrates except mammals. An inability of mammalian supporting cells to proliferate and regenerate hair cells is a main reason why humans are unable to restore hearing or balance function after hair cell death. We aim to uncover the mechanisms that restrict the proliferative capacity of mammalian supporting cells to identify and characterize new drug targets that promote regeneration of the inner ear sensory epithelium. To this end, we will study the molecular mechanisms preventing YAP-TEAD-mediated cell cycle reentry in adult supporting cells. We hypothesize that YAP is differentially covalently modified in adult and neonatal mouse utricles and, therefore, bind to different sets of transcription factors/co-regulators. To verify our hypothesis, we propose the following set of experiments: 1. Identify specific covalent modifications that control association of YAP with different transcription factors/co-regulators. 2. Generate and select clones to produce monoclonal antibodies that will recognize YAP only when it is modified on specific residue. 3. Analyze a correlation between specific YAP modifications, TEAD/BRD4 binding specificity and ability to reenter the cell cycle. We believe the data obtained will allow developing a strategy to reprogram adult supporting cells to convert them into progenitor/stem-like cells by manipulating YAP-TEAD transcriptional activity.
Short titleSignaling pathways preventing cell cycle re-entry in supporting cells of the mouse utricle
StatusActive
Effective start/end date1/1/2012/31/22

Fingerprint

Saccule and Utricle
Cell Cycle
Hearing
Vertebrates
Transcription Factors
Stem Cells
Epithelium
Aptitude
Organized Financing
Inner Ear
Regeneration
Mammals
Cell Death
Clone Cells
Monoclonal Antibodies

Keywords

  • hair cells, supporting cell, utricle, cell cycle, YAP, covalent modifications, TEAD