Project ID CM-HD2023_49

ThemeCM-HD

Co Supervisor 1A FoCOCS, Centre for Craniofacial & Regenerative BiologyWebsite

Co Supervisor 1B FoLSM, Twin Research and Genetic EpidemiologyWebsite

Harnessing novel molecular tools to understand the causes of age-related hearing loss

More than 50% of people aged over 65 have age-related hearing impairment (ARHI). ARHI has considerable impact on health and well-being, from mild difficulty with communication to depression, social isolation and dementia. ARHI is heritable (h2=40%) but the underlying genetic and molecular causes are poorly understood, limiting development of new therapeutics. Our recent large genome-wide association (GWAS) meta-analysis has identified many new candidate loci: their further exploration requires an understanding of the molecular architecture of the cochlea.

This interdisciplinary project combines state-of-the-art molecular approaches for transcriptional and epigenomic profiling, bioinformatic analysis with in vitro studies examining the molecular and cellular function of specific genes expressed in the cochlea. It will equip the student with the technical and intellectual skills to design and conduct multidisciplinary research, as well as to defining pathogenic mechanisms in common complex traits.

Year 1. Collection and processing human cochlea (removed during posterior fossa tumour surgery) for single cell multi-omics analysis. The student will receive training in molecular methods and data analysis.
Year 2. Defining cellular diversity in the cochlea, characterizing cell types and identifying gene expression by cell type, as well as the non-coding regions controlling gene expression. In parallel, the student will learn ear organoid culture from human stem cells.
Years 3 and 4. Functional experiments and writing up: the lead candidate variants will be investigated in organoids using imaging, microscopy and molecular approaches.

The project uses complementary expertise of both supervisors, clinical support for tissue collection and all materials and methods are currently available.

One representative publication from each co-supervisor:

• Buzzi, A.L., Chen,J., Thiery,A., Delile, J. and Streit, A. 2022. Sox8 remodels the cranial ectoderm to generate the ear. PNAS in press; preprint: https://www.biorxiv.org/content/10.1101/2021.04.20.440617v2.article-info

• Trpchevska et al. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss. American Journal Human Genetics 2022 Jun 2;109(6):1077-1091. PMID: 35580588. DOI: 10.1016/j.ajhg.2022.04.010