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: 10416091
• 负责人: Xue Yuan
• 金额: $ 24.89万
• 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/10416091
• 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.

项目摘要/摘要 口腔粘膜容易发生创伤，先天性缺陷和获得性疾病（例如癌症）等疾病。 同时，口服粘膜是保护基础组织的障碍，这是通过 不断替代源自基础层干细胞储层的细胞。现在， 干细胞在口服粘膜中的身份在很大程度上是未知的，从而阻止了进一步的机械研究 阐明他们的自我更新，差异化和再生能力。我已经开发了转基因的曲目 谱系追踪小鼠并鉴定出作为口服干细胞库的WNT响应群体 上皮。在这个拟议的项目中，我将彻底描述这些Wnt响应词干的贡献 体内平衡期间口腔粘膜中的细胞（AIM1），损伤修复（AIM2）和恶性肿瘤（AIM3）。我的中央假设 - ESI是在口服粘膜中，Wnt响应性细胞保持组织完整性并影响再生 受伤后，同一人群的突变会引发口腔癌。这些目标将利用谱系跟踪， 谱系消融，标签保留和损伤和口腔癌模型，以询问干细胞维持，再生 癌症中的动力学以及起源细胞。这些研究旨在丰富我们的知识 关于干细胞在口服粘膜中的分布以及这些细胞如何促进完整性和愈合 口服粘膜的能力。该研究的领域具有巨大的潜力，可以革新治疗方法 颅面复合物中组织的再生，包括皮肤和粘膜。成功完成 项目还将提高我们对癌症干细胞的了解，从而为口腔癌治疗提供新的靶标。 AIM 2和3将在吉尔·赫尔姆斯博士（斯坦福大学）的指导下启动，丹尼尔·拉莫斯博士 （UCSF）和Sinha Satrajit博士（布法罗大学），并在R00期间完成，而AIM 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助理教授的职位。我打算 制定依靠最先进的遗传鼠标模型来解决未​​解决的独立研究计划 口腔粘膜中的问题与人类健康明显相关。除了专门的研究时间，我还将 课程工作并参加研讨会，以更新我在干细胞生物学快速发展的领域的知识和 斯坦福大学的癌症生物学，该大学拥有经验最丰富，最繁荣的社区之一 世界上的癌症和干细胞生物学家。我还将学习高级生物统计学以改善实验设计 和数据解释。为了过渡到寻求R01级资金的独立调查员， 我将积极从事我的导师的赠款，教学，指导和沟通技巧 以及顾问，以及斯坦福大学提供的互动讲座和教练课程。