Delineating epigenetic coordination of regenerative tissue plasticity Abstract: Tissue damage and repair represent fundamental problems in human health for which few pharmacological interventions are available. In stratified epithelium, regeneration involves the integration of complex molecular networks at both the single cell and tissue-scale level. These networks largely consist of epigenetic modifiers that function to direct cell state plasticity and lineage fate in response to injury. Such changes must also be integrated with intraepithelial tissue-resident immunity for full tissue regeneration. Despite progress in understanding the cellular pathways that mediate epithelial renewal, there is a significant gap in understanding how the distinct epigenetic states of various epithelial cell subtypes cooperate with tissue-resident immune cells to mediate a tissue-scale restorative response. This gap considerably limits our ability to design therapeutic strategies for a broad range of human diseases including wound healing, lung diseases, tissue fibrosis, cancer, and immune disorders.
The aim of my research is to functionally understand the basic epigenetic modifiers that govern epithelial-immune cross talk during tissue regeneration, and how these modifiers contribute to the orchestration of multiple epithelial lineages across the regenerating stratified epithelium. Toward this aim, I have developed a novel in vivo gene editing platform to simultaneously manipulate and interrogate district epithelial cell lineages. I employ this tool for high resolution functional dissection of the epigenetic networks operating to mediate immune-epithelial cross-talks during regenerative healing. The accessibility of the skin and tongue epidermis, and the abundance of tissue-resident immune cells in these tissues, makes them ideal model systems for these studies. Dr. Matthew Ramsey?s laboratory and mentorship provides an excellent environment for me to gain experience in sophisticated in vivo tissue stem cell techniques, and in to acquire the necessary mentoring skills necessary to transition to independence. Co- mentorship by Dr. Tomas Kupper, an established expert in epithelial tissue-resident T cell immunology, will provide me with the exceptional epithelial tissue-resident immunology training necessary to establish an independent research program distinct from my mentors. My career development plan integrates additional laboratory training, specialized course in epigenetics, immunology, and large-data analysis at the world-class environment of Harvard Medical School. To assist with science- and career-related decisions, I have assembled an Advisory Committee composed of a team of established experts and ongoing collaborators. I have equally designed a tailored diversity and inclusion training plan outlining objectives to attain during the K99 phase. The proposed studies and mentoring plans described in this proposal will provide me with a robust training platform to launch my independent academic research career.
The stratified epithelium is the most complex epithelial architecture among living systems and is most often subject to wounding and damage. Regeneration in this complex tissue requires multifaceted synchronization of several epithelial cell lineages and local tissue immune cells. My studies aim to functionally understand the epigenetic factors and pathways that regulate full tissue restoration in the stratified mammalian epithelium.