Identification and characterization of transcription factors with key roles in inner ear development:

Disabling hearing loss afflicts over 50% of the population over the age of 70 and the final common pathway of most forms of hearing loss involves the loss of hair cells, the sensory cells of the ear. Our team takes a cell type-specific multi-omic approach to identify key regulators of cell type-specific differentiation in the ear, which could later be applied towards hair cell regeneration. Four of our key findings have been the identification of ZEB1 and miR-200b as the major determining factors of epithelial fate in the ear; RFX1 and RFX3 as transcription factors that are necessary for the terminal differentiation and survival of early postnatal auditory hair cells in mice; IKZF2 as a regulator of outer hair cell functional maturation; and most recently, the molecular mechanism by which GFI1 promotes hair cell differentiation during early development (‘GFI1 functions to repress neuronal gene expression in developing hair cells’ manuscript in preparation). RFX and IKZF2 are amongst very few regulators that have been shown to play a role in hair cell terminal differentiation – a necessary step for successful hair cell regeneration.

Development and application of approaches for cell type-specific analysis in the ear and data sharing: The inner ear sensory epithelium is complex and consists of multiple cell types. Cell type-specific analyses are helpful in defining the regulatory pathways that determine cell fate. In order to define cell type-specific regulatory pathways in inner ear development, we characterized the expression of transmembrane cell surface proteins (CD proteins) in the inner ear. We subsequently identified combinations of markers that could allow for inner ear cell type-specific isolation using flow cytometry. We continue to develop and apply new approaches for cell type transcriptome and translatome analysis in the ear in both mouse and zebrafish and are actively involved in their dissemination in the field. Finally, we developed and maintain the gEAR portal (gene Expression Analysis Resource umgear.org), a website for cell type-specific visualization, sharing and analysis. The gEAR portal has now turned into a primary site for multi-omic data sharing for researchers in the ear field and has been cloned to serve additional research communities (e.g., nemoanalytics.org for neuroscience).

The POU4F3 and GFI1 transcriptional cascades in hair cell development: POU4F3 is an inner ear hair cell-specific transcription factor that is expressed in the hair cells shortly after they are formed. Mutations in POU4F3 underlie human hereditary hearing loss. In the mouse, loss of Pou4f3 results in early degeneration of all inner ear hair cells. My graduate thesis work focused on identification and characterization of the targets of POU4F3 in hair cells. Several of these targets have been subsequently identified to be important for hearing in human (LHX3) or critical for increasing the efficiency of transforming stem cells to hair cells (GFI1). My laboratory now continues to study the function of the GFI1 signaling cascade in hair cell development.

Understanding the molecular basis of noise induced hearing loss (NIHL) and sex differences in hearing – a step towards therapeutics: NIHL afflicts 5% of the population worldwide. To date there are no effective interventions to prevent or treat NIHL. Through a project funded by the Department of Defense we worked towards developing the blueprint of the cell type-specific molecular changes that occur as a result of NIHL, we have shared many of the results pre-publication, as podium or poster presentations (manuscripts in preparation). However, in the process of performing the NIHL studies we identified striking sex-related differences in the response of male and female mice to noise trauma and its possible treatments. We are actively studying the molecular basis of sex differences in hearing, have published and shared some of our results, and plan to harness our findings to develop novel therapeutic interventions.    

Identification and characterization of genes that function in inner ear development and underlie hearing and balance disorders in human and in mice: Hereditary hearing loss is highly heterogeneous with over 150 genes estimated to underlie congenital non-syndromic hearing loss. The significance in identification of genes that underlie hereditary hearing loss is purely translational. As more genes are identified, patients can get better genetic counseling, and in the future, personally-tailored hearing restoration. My work on the identification of genes that underlie hearing loss ranges from projects that I spearheaded, using ENU-induced mouse mutants, to contributions to collaborative projects in human or mouse. Our recently identified hair cell-enriched transcripts in mouse, have been translated into a diagnostic discovery panel in collaboration with Richard Smith, PhD (as part of NIH R01, DC003544).