Otic Guidance

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Project Summary / Abstract The first aim of this research proposal is to use single-cell transcriptomics to describe the changes in gene expression that happen during otic guidance from pluripotent stem cells. It builds on known principles of inner ear development and utilizes single-cell RNA-Seq and computational modeling for extracting the differentiation pathway of cells towards non-neural ectoderm, pre-placodal ectoderm, and ultimately otic induction and the sensory hair cell lineage. In a second aim, it is proposed to comparatively investigate the distinct steps when otic guidance from embryonic stem cells fails, which is a common problem. The generation of inner ear cells from embryonic stem cells is an unreliable enterprise and has hampered research for more than a decade. Computational comparisons of gene expression changes in successfully guided inner ear lineage cells with lineages that stray from otic differentiation will result in the identification of specific signaling pathways that contribute to cell differentiation failures. Based on computational modeling, testable hypotheses will be generated and experimentally validated. The ultimate goal of the proposed research is the elimination of experimental variations of otic guidance from stem cells towards establishing a reliable otic guidance protocol that can be widely utilized by many laboratories.