Regulation of Cell Polarity During Epidermal Growth and Homeostasis

这项提案的长期目标是了解在细胞周期中调节细胞极性的机制。 表皮生长和再生。细胞极性是指细胞间连接的不均匀分布， 细胞骨架结构和细胞器内的细胞，是最基本的建筑特征， 上皮组织当细胞极性受损时，细胞会变得形状异常，方向错误， 不适当地分层，导致增殖、分化和肿瘤发生的异常控制。在高度 再生成人上皮组织如皮肤，干细胞的失调被认为是一种 这是上皮癌的根本原因，因此维持细胞极性和组织结构至关重要 因为皮肤细胞不断地分裂、分化和死亡。虽然细胞极性的建立是相当好的 尽管如此，人们对组织再生过程中极性是如何调节的知之甚少。因为 哺乳动物的皮肤是自然界中最引人注目的极化和再生组织之一，它是理想的 系统来研究再生过程中极性的调节。利用这个系统我找到了一本小说 在表皮干细胞有丝分裂过程中极性蛋白空间分布的控制机制。 在有丝分裂过程中，极性蛋白从质膜内化到细胞质膜 囊泡，在胞质分裂期间转运回质膜并以极化方式重新定位。 这种机制对于正确维持整个表皮的组织极性至关重要。的 该提案的独立/ROO阶段的中心目标是破译调节细胞的机制， 极性作为细胞进行有丝分裂，以及这些途径的失调如何影响组织结构， 增殖和分化。具体来说，我将1）阐明控制机制。内化 极性蛋白质在细胞分裂过程中; 2）确定新的基因的极性维持过程中必不可少的 有丝分裂;和3）定义极性如何在有丝分裂后的子细胞中重建。破译 调节增殖性表皮干细胞极性的机制对于本领域的研究将是至关重要的。 长期目标是了解极性维持的缺陷如何导致人类疾病。

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 establishment of cell polarity is fairly well understood, less 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. Using this system I have identified a novel mechanism controlling the spatial distribution of polarity proteins in epidermal stem cells undergoing mitosis. During mitosis, polarity proteins are internalized from the plasma membrane into cytoplasmic membrane vesicles, transported back to the plasma membrane during cytokinesis and relocalized in polarized manner. This mechanism is essential for the proper maintenance of tissue-wide polarity across the epidermis. The central aim of the independent/ROO phase of this proposal is to decipher the mechanisms that regulate cell polarity as cells undergo mitosis and how dysregulation of these pathways affect tissue architecture, proliferation and differentiation. Specifically, I will 1) elucidate the mechanisms controlling.the internalization of polarity proteins during cell division; 2) identify novel genes essential for polarity maintenance during mitosis; and 3) define how polarity is re-established in post-mitotic daughter cells. Deciphering 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.