Delineating epigenetic coordination of regenerative cell plasticity

再生组织可塑性的表观遗传协调性研究 摘要：组织损伤和修复是人类健康的基本问题，很少有人能做到。 药物干预措施是可用的。在复层上皮中，再生涉及整合 单细胞和组织规模的复杂分子网络。这些网络主要包括 表观遗传修饰物，其功能是指导细胞状态的可塑性和世系命运，以响应伤害。是这样的 改变还必须与上皮内组织驻留免疫相结合，以实现充分的组织再生。 尽管在了解介导上皮细胞更新的细胞通路方面取得了进展，但仍有显著的 理解不同上皮细胞亚型的不同表观遗传状态如何协同作用的差距 组织驻留的免疫细胞，以调节组织规模的恢复性反应。这一差距大大限制了我们的 有能力为多种人类疾病设计治疗策略，包括伤口愈合、肺 疾病、组织纤维化、癌症和免疫紊乱。我研究的目的是从功能上理解 在组织再生过程中控制上皮免疫串扰的基本表观遗传修饰物，以及如何 这些修饰物有助于协调再生层化的多个上皮谱系 上皮组织。为此，我开发了一种新颖的体内基因编辑平台，以同时 操纵和盘问区域上皮细胞谱系。我使用这个工具来实现高分辨率的泛函 再生过程中调节免疫-上皮性交叉对话的表观遗传网络的解剖 治愈。皮肤和舌上皮的可达性，以及组织驻留免疫细胞的丰富性 在这些组织中，使它们成为这些研究的理想模型系统。马修·拉姆齐博士的实验室和 导师为我提供了一个极好的环境，让我在复杂的活体组织干细胞方面获得经验 细胞技术，以及获得过渡到独立所需的必要指导技能。共同-- 托马斯·库珀博士是上皮组织驻留T细胞免疫学方面的知名专家，他的指导将 为我提供特殊的上皮组织常驻免疫学培训，以建立 独立研究项目，有别于我的导师。我的职业发展计划包括其他 世界一流的实验室培训、表观遗传学、免疫学和大数据分析专业课程 哈佛医学院的环境。为了帮助做出与科学和职业相关的决定，我有 组建了一个咨询委员会，由一组公认的专家和持续的合作者组成。我 同样设计了量身定制的多样性和包容性培训计划，概述了在 K99相。本提案中描述的拟议研究和指导计划将为我提供一个强有力的 培训平台开启了我的自主学术研究生涯。

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.