Delineating epigenetic coordination of regenerative cell plasticity

描绘再生细胞可塑性的表观遗传协调

• 批准号: 10676409
• 负责人: Yvon Woappi
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676409
• 关键词: 3-Dimensional; Advisory Committees; Architecture; Biological Assay; Biological Models; Cell Lineage; Cells; Complex; Cutaneous; Data Analyses; Development Plans; Dissection; Dorsal; Dropout; Environment; Epidermis; Epigenetic Process; Epithelial; Epithelial Cells; Fibrosis; Genes; Growth; Guide RNA; Harvest; Health; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunocompetent; Immunohistochemistry; Immunology; Impairment; Injury; Intervention; Keratin; Knowledge; Laboratories; Lead; Lung diseases; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Mentorship; Molecular; Mucous Membrane; Mus; Natural regeneration; Organism; Pathway interactions; Pharmacology; Phase; Population; Process; Regenerative response; Research; Resolution; Role; Science; Shapes; Signal Transduction; Site; Skin; Stains; Stratified Epithelium; Stress; T-Lymphocyte; Techniques; Therapeutic; Thick; Time; Tissues; Tongue; Training; Work; career; career development; cell type; design; diversity and inclusion; epithelial stem cell; epithelium regeneration; experience; experimental study; healing; human disease; in vivo; injured; intraepithelial; keratinocyte; laboratory experience; medical schools; next generation sequencing; novel; post-doctoral training; progenitor; programs; reconstruction; recruit; regenerative; regenerative cell; regenerative tissue; repaired; response; response to injury; restoration; skills; tissue regeneration; tissue stem cells; tool; wound; wound healing

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.

再生组织可塑性的表观遗传协调 翻译后摘要：组织损伤和修复代表了人类健康的基本问题， 药物干预是可用的。在复层上皮中，再生涉及整合 在单细胞和组织水平上的复杂分子网络。这些网络主要包括 表观遗传修饰剂，其作用是指导细胞状态可塑性和响应损伤的谱系命运。等 改变还必须与上皮内组织驻留免疫结合以实现完全组织再生。 尽管在理解介导上皮更新的细胞途径方面取得了进展，但仍存在显著的 在理解各种上皮细胞亚型的不同表观遗传状态如何与 组织驻留免疫细胞来介导组织规模的恢复性反应。这一差距大大限制了我们的 能够为广泛的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剂，以及如何 这些修饰剂有助于跨再生分层的上皮细胞的多个上皮谱系的协调 上皮为此，我开发了一种新型的体内基因编辑平台， 操纵和询问区域上皮细胞谱系。我使用此工具进行高分辨率功能 解剖再生过程中介导免疫-上皮交叉对话的表观遗传网络 治愈皮肤和舌表皮的可及性，以及组织驻留免疫细胞的丰富性 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 导师制为我提供了一个很好的环境，使我在复杂的体内组织干细胞方面获得经验。 细胞技术，并在获得必要的辅导技能过渡到独立。共- 托马斯Kupper博士，在上皮组织常驻T细胞免疫学的专家，将指导 为我提供特殊的上皮组织居民免疫学培训，以建立一个 独立的研究项目，与我的导师不同。我的职业发展计划包括额外的 实验室培训，表观遗传学，免疫学和世界一流的大数据分析专业课程 哈佛医学院的环境。为了帮助科学和职业相关的决策，我 成立了一个咨询委员会，由知名专家和长期合作者组成。我 同样设计了一个量身定制的多样性和包容性培训计划，概述了在 K99阶段。本提案中所述的拟议研究和指导计划将为我提供一个强大的 培训平台，开始我独立的学术研究生涯。