Integrative Systems Biology of Hearing Restoration
Seth Ament, Ph.D., University of Maryland School of Medicine

The broad premise of the HRP is to identify molecules that could control hair cell regeneration. To do this, we are studying cell types and regenerative processes in multiple contexts and species, then integrating these data together to identify mechanisms that could potentially be turned on in the mouse cochlea to drive transdifferentiation (activating the correct set of hair cell–promoting genes in supporting cells). The role of this systems biology project is to provide the necessary data integration “glue,” binding together the results from the data generation projects. We will combine much of the data that is being generated by the HRP to advance our knowledge of hair cells, supporting cells, conversion of one cell type to another, and the potential for regeneration. By modeling all of the available HRP data, we will identify regulatory molecules that may contribute to regeneration.

Integrative Systems Biology of Hearing Restoration
Seth Ament, Ph.D., University of Maryland School of Medicine

This project will focus on integrating multiple datasets from the HRP to gain insight into hair cell development and regeneration and prioritize specific "driver" genes that can be targeted to induce regeneration. The main premise is that we will be able to regenerate hair cells if we activate the correct set of hair cell–promoting genes in supporting cells. This process is called transdifferentiation, and it occurs naturally in species such as birds and fish, but not in the inner ear of adult mammals. HRP researchers have generated numerous genomic datasets that describe cochlear development and transdifferentiation in multiple species. By analyzing all of these data together using sophisticated network analysis tools, we aim to identify which genes are involved in these processes as well as key differences that may explain the inability of human and mouse cells to transdifferentiate. Finally, this will enable the identification of genes that can be targeted to enable transdifferentiation.

Integrated systems biology of hearing restoration
Seth Ament, Ph.D., University of Maryland School of Medicine

The goal of this proposal is to support the HRP through data integration and systems biology. We propose two related goals for 2018, based on our preliminary network modeling results and discussions with other HRP investigators. We will (a) predict regulatory genes driving cell fate decisions in the developing mouse cochlea using refined transcriptional regulatory networks, gene co-expression networks, protein-protein interaction networks, and related methods. We will (b) extend these analyses to the zebrafish and chick models by projecting networks from the mouse cochlea onto data from these other species. Our goal is to generate testable predictions about driver genes and perturbations (deviations) that could influence hearing restoration.