Mark Warchol Ph.D.

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Integrative Analysis

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Integrative Analysis
Seth Ament, Ph.D. (co-chair), University of Maryland
Ronna Hertzano, M.D., Ph.D. (co-chair), National Institute on Deafness and Other Communication Disorders
Albert Edge, Ph.D., Mass Eye & Ear
Stefan Heller, Ph.D., Stanford University
David Raible, Ph.D., University of Washington
Jennifer Stone, Ph.D., University of Washington

This group will take the lead on data curation and analysis. A dedicated full-time HRP analyst is working across groups to help collect and process data, thereby facilitating a broader analysis of cell states and trajectories across species. The group will start by annotating hair cell types from all species so that anyone in the field can assess what kind of hair cell their regeneration approaches may produce, while also easing identification of common hair cell genes, which will help the Cross-Species Epigenetics group. Analysis of the hair cells produced in mouse organoids will be performed as an example. The Ament lab will leverage their expertise in bioinformatics, while the Hertzano lab will continue to oversee upkeep of gEAR, with a goal of making it even easier for HRP members to post their new data and for others in the community to analyze those data. The Edge lab will take the lead on the development of organoids as a screening platform for the future. The Heller, Hertzano, Raible, and Stone labs will validate markers by in situ hybridization across species, and all working group members will help direct the analysis.

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Identification of Candidate Regulators of Hair Cell Regeneration in the Chick Cochlea and Utricle

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Identification of candidate regulators of hair cell regeneration in the chick cochlea and utricle
Jennifer Stone, Ph.D. University of Washington
Mark Warchol, Ph.D. Washington University in St. Louis

This project has two components. In the first, the investigators will focus on validation of miRNA-seq data recently acquired by the HRP consortium; these new experiments will determine whether the genomics experiments accurately reflected miRNA fluctuations in the tissue, and may suggest candidate miRNA modulators of hair cell regeneration. In the second component, this project will test which specific signaling pathways are important for the proliferation of supporting cells and the regeneration of hair cells using pharmacological approaches.

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Transcriptomics-based Analysis of Hair Cell Regeneration in Non-Mammals

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Transcriptomics-based analysis of hair cell regeneration in non-mammals
Stefan Heller, Ph.D. Stanford University
Tatjana Piotrowski, Ph.D. Stowers Institute for Medical Research
Jennifer Stone, Ph.D. University of Washington
Mark Warchol, Ph.D. Washington University in St. Louis
Michael Lovett, Ph.D. Imperial College London

In this third-year project, we will disrupt hair cells, then analyze how gene expression changes in single cells from species that show robust hair cell regeneration. Heller’s lab will examine the consequences of aminoglycoside damage at the single-cell level in the chick utricle, while the Piotrowski lab will examine fish lateral-line cells. In another component, the project will add two time points to the chick cochlea and utricle bulk RNA-seq datasets that were generated by Lovett and Warchol and which are extremely valuable datasets for the HRP consortium.

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Single-cell transcriptional profiling of chicken utricle and Basilar Papilla Sensory Epithelium Cells After Aminoglycoside-induced Hair Cell loss

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Single-cell transcriptional profiling of chicken utricle and basilar papilla sensory epithelium cells after aminoglycoside-induced hair cell loss
Stefan Heller, Ph.D. Stanford University School of Medicine
Jennifer S. Stone, Ph.D. University of Washington
Michael Lovett, Ph.D. Imperial College London
Mark Warchol, Ph.D. Washington University 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.

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Putative Hybrid Cells in Damaged Adult Organ of Corti

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Putative hybrid cells in damaged adult organ of Corti
Albert Edge, Ph.D. Massachusetts Eye and Ear Infirmary, Harvard Medical School
Jennifer S. Stone, Ph.D. University of Washington
Mark Warchol, Ph.D. Washington University School of Medicine
Liz Oesterle, Ph.D. University of Washington
Edwin Rubel, Ph.D. University of Washington

At the fall 2014 HRP meeting, several investigators shared unpublished data and all realized that they had seen the same phenomenon—in the mature mouse inner ear, after damage that wiped our hair cells, a number of cells could be detected that had molecular signatures of hair cells yet still maintained a morphology similar to supporting cells. These hybrid cells could be supporting cells that have partially differentiated towards hair cells, and the group will characterize them in more depth. The project is exciting as it shows that there is some supporting cell response to damage and because we will be able to determine more precisely where the molecular block to full hair cell regeneration occurs.

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Comparative MiRNA Profiling of the Postnatal Mouse Cochlea and Regenerating Avian Basal Papilla

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Comparative miRNA profiling of the postnatal mouse cochlea and regenerating avian basal papilla
Michael Lovett, Ph.D. Imperial College London
Neil Segil, Ph.D. University of Southern California
Mark Warchol, Ph.D. Washington University School of Medicine

Micro RNAs (miRNAs) are small molecules that are transcribed from genomic DNA but not translated into protein. They provide regulation to many processes, uniquely affecting many genes simultaneously. This feature makes miRNA regulation of hair-cell regeneration a particularly interesting target for pharmacological intervention. This project will examine miRNA expression in the inner ears of mice and chicks, and determine the differences in response to hair-cell damage between organs that regenerate their hair cells (chick basilar papilla) and those that do not (mouse cochlea).

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Single Cell Transcriptional Profiling of Chicken Utricle and Basilar Papilla Sensory Epithelium Cells After Aminoglycoside-Induced Hair Cell Loss

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Single cell transcriptional profiling of chicken utricle and basilar papilla sensory epithelium cells after aminoglycoside-induced hair cell loss
Stefan Heller, Ph.D. Stanford University School of Medicine
Mark Warchol, Ph.D. Washington University School of Medicine
Jennifer S. Stone, Ph.D. University of Washington
Michael Lovett, Ph.D. Imperial College London

While the HRP has excellent datasets showing the response of chicken auditory and vestibular cells to damage, the experiments examine all cells (including both hair cells and supporting cells) and are not temporally precise. In these experiments, the investigators will damage hair cells, then examine the molecular responses of hundreds of individual cells. Bioinformatics techniques will allow them to order those cells along a timeline that will reveal the molecular changes that unfold during hair cell regeneration.

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