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

项目总结/摘要 口腔粘膜易于发生诸如创伤、先天性缺陷和获得性疾病（例如，癌症）。 同时，口腔粘膜作为保护下层组织的屏障，这是通过 源自基底层中干细胞的假定储库的细胞的连续替换。目前， 口腔粘膜中干细胞的身份在很大程度上是未知的，这阻碍了进一步的机制研究，以充分了解干细胞的功能。 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的 谱系追踪小鼠，并确定了一个Wnt响应人群，作为干细胞库的功能，在口腔 上皮细胞在这个提议的项目中，我将彻底描述这些Wnt响应干细胞的贡献。 口腔粘膜内稳态（Aim 1）、损伤修复（Aim 2）和恶性肿瘤（Aim 3）期间的细胞。我的中心假设- 在口腔粘膜中，Wnt应答细胞维持组织完整性并实现再生 在损伤后，同一群体的突变引发口腔癌。这些目标将利用血统追踪， 谱系消融，标记保留，损伤和口腔癌模型，以询问干细胞的维持，再生， 在癌症的起源中，细胞的增殖动力学以及细胞。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。这一未充分研究的领域具有巨大的潜力，可以彻底改变治疗方法， 颅面复合体中的组织再生，包括皮肤和粘膜。成功完成本 该项目还将推进我们对癌症干细胞的认识，为口腔癌治疗提供新的靶点。 目标2和3将在吉尔·赫尔姆斯博士（斯坦福大学）、丹尼尔拉莫斯博士 （UCSF）和Sinha Satrajit博士（布法罗大学），并在R 00期间完成，而目标1将 在K99阶段结束前完成。这个项目旨在促进我的职业目标， 在顶级学术研究机构获得终身助理教授的职位。我计划 开发一个独立的研究项目，依靠最先进的遗传小鼠模型来解决未解决的问题。 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，我将采取 课程和参加研讨会，以更新我在干细胞生物学的快速发展领域的知识， 癌症生物学在斯坦福大学举办的最有经验和繁荣的社区之一， 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 数据解释。为了准备过渡到一个追求R 01级资金的独立调查员， 我将积极地从我的导师那里学习基金撰写、教学、指导和沟通技巧 和顾问，以及来自斯坦福大学提供的互动讲座和辅导课程。

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.