The role of Bmi1 in regulation of dental stem cells

描述(申请人提供)：牙齿生物工程非常感兴趣，因为龋齿和牙齿脱落是一个重要的公共卫生问题。此外，牙齿异常在许多颅面综合征中很常见，口腔的易达性使牙齿成为器官置换的极佳测试案例。彻底了解驱动牙齿更新和再生的分子过程将是建造新牙齿的关键。我们正在使用小鼠切牙作为一个模型，以了解干细胞促进牙齿组织更新的机制，因为由于成体干细胞的存在，干细胞可以持续生长。在这项应用中，我们建议通过重点研究Bmi1如何调控这一过程来了解干细胞驱动的牙齿更新在小鼠切牙中的转录控制作用。BMI1是多个组织中干细胞自我更新所必需的聚梳组蛋白。申请中提出的实验将首先使用遗传谱系追踪方法确定门牙中哪些分化细胞类型来自表达Bmi1的干细胞。接下来，我们将探讨Bmi1在体内和体外对切牙干细胞自我更新和分化的功能作用。最后，我们将确定Bmi1的遗传靶点，并确定它们在牙齿干细胞中的功能。这些研究将增进我们对自然界通常如何使用干细胞进行牙齿再生的理解。这些信息将为以干细胞为基础的牙齿生物工程的未来努力提供信息。 公共卫生相关性：牙齿生物工程引起了人们的极大兴趣，因为龋齿和牙齿脱落是一个重要的公共卫生问题。彻底了解驱动牙齿再生的分子过程将是建造新牙齿的关键。我们建议通过重点研究一种名为Bmi1的基因如何调控这一过程，来了解转录控制对干细胞驱动的牙齿更新的自然作用。对于这些研究，我们将使用啮齿动物门牙作为模型系统。

DESCRIPTION (provided by applicant): Tooth bioengineering is of great interest, because dental decay and tooth loss constitute an important public health issue. Additionally, tooth anomalies are common in many craniofacial syndromes, and the easy accessibility of the oral cavity makes teeth an excellent test case for organ replacement. A thorough understanding of the molecular processes that drive tooth renewal and regeneration will be crucial to efforts to build new teeth. We are using the mouse incisor as a model for understanding the mechanisms that underlie the ability of stem cells to contribute to renewal of dental tissues, because it grows continuously due to the presence of adult stem cells. In this application, we propose to learn about the role of transcriptional control of stem cell-driven tooth renewal in the mouse incisor by focusing on how Bmi1 regulates this process. Bmi1 is a Polycomb Group (PcG) protein that is required for stem cell self-renewal in multiple tissues. The experiments proposed in the application will first identify which differentiated cell types in the incisor arise from Bmi1- expressing stem cells using genetic lineage tracing approaches. Next, we will explore the functional role of Bmi1 in incisor stem cell self-renewal and differentiation in vivo and in vitro. Finally, we will identify genetic targets of Bmi1 and determine their function in dental stem cells. These studies will advance our understanding of how nature normally uses stem cells in dental regeneration. Such information will inform future efforts aimed at stem cell-based tooth bioengineering. PUBLIC HEALTH RELEVANCE: Tooth bioengineering is of great interest, because dental decay and tooth loss constitute an important public health issue. A thorough understanding of the molecular processes that drive tooth regeneration will be crucial to efforts to build new teeth. We propose to learn about the natural role of transcriptional control of stem cell- driven tooth renewal by focusing on how a gene called Bmi1 regulates this process. For these studies, we will use the rodent incisor as a model system.