Regulation of Cell Polarity During Epidermal Growth and Homeostasis

描述（由申请人提供）：本提案的长期目标是了解表皮生长和再生过程中调节细胞极性的机制。细胞极性是指细胞内细胞间连接、细胞骨架结构和细胞器的不均匀分布，是上皮组织最基本的结构特征。当细胞极性受损时，细胞变得形状异常、方向错误和分层不当，导致增殖、分化和肿瘤发生的异常控制。在高度再生的成人上皮组织如皮肤中，干细胞的失调被认为是上皮癌的根本原因，因此随着皮肤细胞不断分裂、分化和死亡，细胞极性和组织结构得以维持至关重要。虽然控制细胞极性建立的分子和机制已相当清楚，但对组织再生过程中极性如何调节知之甚少。哺乳动物皮肤是自然界中最具极性和再生能力的组织之一，是研究再生过程中极性调控的理想系统。我的初步数据确定了一种新的机制，控制极性蛋白的空间分布在表皮干细胞进行有丝分裂。我推测，上皮细胞的极性在生长和再生过程中，通过细胞周期依赖性的极性蛋白定位的调节。为了验证这一中心假设，我将：1）描述有丝分裂过程中极性蛋白定位的空间和时间动态; 2）定义有丝分裂过程中控制极性蛋白动态的机制; 3）确定有丝分裂表皮细胞中极性的调节如何有助于维持整体组织结构。有丝分裂过程中极性蛋白定位的动力学和机制将在指导阶段确定，并在独立阶段完成对新确定的机制和蛋白质相互作用的后续研究。阐明调节增殖性表皮干细胞极性的机制对于理解极性维持缺陷如何导致人类疾病的长期目标至关重要。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand the mechanisms that regulate cell polarity during epidermal growth and regeneration. Cell polarity refers to the unequal distribution of cell-cell junctions, cytoskeletal structures and organelles within the cell, and is the most fundamental architectural feature of epithelial tissues. When cell polarity is compromised cells become aberrantly shaped, misoriented, and improperly layered, leading to aberrant control of proliferation, differentiation and tumorigenesis. In highly regenerative adult epithelial tissues such as the skin, dysregulation of stem cells is thought to be an underlying cause of epithelial cancers, so it is critical that cell polarity and tissue architecture is maintained as skin cells continually divide, differentiate and die. While the molecules and mechanisms controlling the establishment of cell polarity are fairly well understood, little is known about how polarity is regulated during tissue regeneration. Because the mammalian skin is one of the most strikingly polarized and regenerative tissues in nature, it is an ideal system to study the regulation of polarity during regeneration. My preliminary data identify a novel mechanism controlling the spatial distribution of polarity proteins in epidermal stem cells undergoing mitosis. I hypothesize that epithelial polarity is maintained during growth and regeneration through cell cycle-dependent regulation of polarity protein localization. To test this central hypothesis I will: 1) characterize the spatial and temporal dynamics of polarity protein localization during mitosis; 2) define the mechanisms controlling polarity protein dynamics during mitosis; and 3) determine how regulation of polarity in mitotic epidermal cells contributes to the maintenance of global tissue architecture. The dynamics and mechanisms of polarity protein localization during mitosis will be identified during the mentored phase, and follow up on newly identified mechanisms and protein interactions will be accomplished during the independent phase. Decifering the mechanisms that regulate polarity in proliferative epidermal stem cells will be fundamentally important to the long-term objective of understanding how defects in polarity maintenance can lead to human disease.