Role of Wnt-responsive cells in oral mucosa homeostasis, injury, and malignancy

Wnt 反应细胞在口腔粘膜稳态、损伤和恶性肿瘤中的作用

• 批准号: 10409912
• 负责人: Xue Yuan
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409912
• 关键词: Ablation; Address; Anatomy; Architecture; Area; Biometry; Buffaloes; Cancer Biology; Cancer Model; Carcinoma; Cell Maintenance; Cell division; Cells; Chemicals; Cicatrix; Communication; Communities; Congenital Abnormality; Data; Data Analyses; Defect; Deterioration; Development; Disease; Educational process of instructing; Epithelial; Epithelial Cells; Funding; Genetic; Goals; Grant; Health; Homeostasis; Human; Injections; Injury; Institution; Knowledge; Label; Lamina Propria; Learning; Left; Location; Malignant - descriptor; Malignant Neoplasms; Maxilla; Mentors; Mentorship; Mission; Mitotic Activity; Morphology; Mouth Neoplasms; Mucous Membrane; Mus; Mutation; National Institute of Dental and Craniofacial Research; Natural regeneration; Oral; Oral Medicine; Oral mucous membrane structure; Periodontal Ligament; Phase; Play; Population; Positioning Attribute; Predisposition; Process; Recurrence; Regenerative capacity; Relapse; Research; Research Personnel; Role; Skin; Squamous cell carcinoma; Stratum Basale; Surface; Tamoxifen; Testing; Therapeutic; Thick; Time; Tissues; Tracer; Transgenic Organisms; Trauma; Universities; Update; Wound models; Writing; cancer cell; cancer stem cell; cancer therapy; carcinogenesis; career; cell type; chemotherapy; craniofacial complex; defined contribution; design; experience; experimental study; healing; improved; injury and repair; interest; keratinization; lectures; malignant mouth neoplasm; migration; mouse model; mouth squamous cell carcinoma; novel; oral cavity epithelium; oral tissue; prevent; professor; programs; regeneration following injury; regenerative; self-renewal; skills; stem; stem cell biology; stem cells; tenure track; tissue regeneration; tissue stem cells; tumor; tumor growth; wound; wound bed; wound healing; wound treatment

Project Summary/Abstract Oral mucosa is prone to disorders such as trauma, congenital defects, and acquired diseases (e.g., cancer). Meanwhile, oral mucosa serves as a barrier to protect the underlying tissues, which is achieved through the continual replacement of cells originating from a presumable reservoir of stem cells in the basal layer. Currently, the identity of stem cells in oral mucosa is largely unknown, preventing further mechanistic studies to fully un- derstand their self-renewal, differentiation and regeneration capacity. I have developed a repertoire of transgenic lineage tracing mice and identified a Wnt-responsive population that functions as a stem cell pool in the oral epithelia. In this proposed project, I will thoroughly characterize the contribution(s) of these Wnt-responsive stem cells in oral mucosa during homeostasis (Aim1), injury repair (Aim2), and malignancy (Aim3). My central hypoth- esis is that in oral mucosa, Wnt-responsive cells maintain the tissue integrity and effectuate the regeneration following injury, and mutation of this same population initiates oral cancer. These aims will utilize lineage tracing, lineage ablation, label retention, and injury and oral cancer models to interrogate stem cell maintenance, regen- erative dynamics as well as the cells of origin in cancer. These studies are designed to enrich our knowledge about the distribution of stem cells in oral mucosa and how those cells contribute to the integrity and healing ability of oral mucosa. This understudied area has great potential to revolutionize the therapeutic approaches for regeneration of tissues in the craniofacial complex, including skin and mucosa. Successful completion of this project will also advance our knowledge of cancer stem cells, providing novel targets for oral cancer treatment. Aim 2 and 3 will be initiated under the mentorship of Dr. Jill Helms (Stanford University), Dr. Daniel Ramos (UCSF) and Dr. Sinha Satrajit (University at Buffalo) and completed during the R00 period, whereas Aim 1 will be completed before the end of the K99 phase. This project has been designed to facilitate my career goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution. I plan to develop an independent research program relying on state-of-the-art genetic mouse models to address unsolved questions in oral mucosa with clear relevance to human health. Besides the dedicated research time, I will take coursework and attend seminars to update my knowledge in the rapidly evolving fields of stem cell biology and cancer biology at Stanford University which hosts one of the most experienced and thriving communities of cancer and stem cell biologists in the world. I will also learn advanced biostatistics to improve experiment design and data interpretation. To prepare for the transition into an independent investigator pursuing R01-level funding, I will be actively engaged in learning grant writing, teaching, mentoring and communication skills from my mentor and advisors, and also from the interactive lectures and coaching sessions offered from Stanford University.

项目概要/摘要 口腔粘膜容易出现外伤、先天缺陷和后天性疾病（例如癌症）等疾病。 同时，口腔粘膜作为保护底层组织的屏障，这是通过 源自基底层中可能的干细胞库的细胞的持续替换。现在， 口腔粘膜中干细胞的身份很大程度上未知，这阻碍了进一步的机制研究以完全阐明 了解它们的自我更新、分化和再生能力。我开发了一套转基因技术 谱系追踪小鼠并鉴定出一个 Wnt 反应群体，该群体在口腔中充当干细胞池 上皮细胞。在这个拟议的项目中，我将彻底描述这些 Wnt 响应干的贡献 口腔粘膜细胞在稳态（Aim1）、损伤修复（Aim2）和恶性肿瘤（Aim3）过程中的作用。我的中心假设—— 其本质是在口腔粘膜中，Wnt反应细胞维持组织完整性并实现再生 受伤后，同一群体的突变会引发口腔癌。这些目标将利用谱系追踪， 谱系消融、标记保留以及损伤和口腔癌模型来询问干细胞的维持、再生 迭代动力学以及癌症起源细胞。这些研究旨在丰富我们的知识 关于干细胞在口腔粘膜中的分布以及这些细胞如何促进口腔粘膜的完整性和愈合 口腔粘膜的能力。这个研究不足的领域具有彻底改变治疗方法的巨大潜力 颅面复合体组织的再生，包括皮肤和粘膜。顺利完成本次 该项目还将增进我们对癌症干细胞的了解，为口腔癌治疗提供新的靶标。 目标 2 和 3 将在 Jill Helms 博士（斯坦福大学）、Daniel Ramos 博士的指导下启动 （UCSF）和 Sinha Satrajit 博士（布法罗大学）并在 R00 期间完成，而目标 1 将 在K99阶段结束之前完成。该项目旨在促进我的职业目标 获得顶级学术研究机构的终身教授助理教授职位。我计划 开发一个独立的研究计划，依靠最先进的基因小鼠模型来解决未​​解决的问题 与人类健康明显相关的口腔粘膜问题。除了专门的研究时间之外，我还会花 课程作业并参加研讨会，以更新我在快速发展的干细胞生物学领域的知识 斯坦福大学的癌症生物学拥有最有经验和最繁荣的社区之一 世界癌症和干细胞生物学家。我还将学习先进的生物统计学来改进实验设计 和数据解释。为了准备过渡为寻求 R01 级资助的独立研究者， 我将积极向导师学习资助写作、教学、指导和沟通技巧 和顾问，以及斯坦福大学提供的互动讲座和辅导课程。