Regulation of Cell Polarity During Epidermal Growth and Homeostasis

这项建议的长期目标是了解在细胞极化过程中调节细胞极性的机制 表皮生长和再生。细胞极性指的是细胞-细胞连接的不均匀分布， 细胞内的细胞骨架结构和细胞器，是 上皮组织。当细胞的极性受到损害时，细胞会变得异常形状、方向错误和 不适当的分层，导致对增殖、分化和肿瘤形成的异常控制。在高度集中 再生的成人上皮组织，如皮肤，干细胞调节失调被认为是 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 因为皮肤细胞不断分裂、分化和死亡。虽然细胞极性的建立是相当好的 然而，对于极性在组织再生过程中是如何被调节的，我们知之甚少。因为 哺乳动物皮肤是自然界中最显著的极化和再生组织之一，它是理想的 研究再生过程中极性调节的系统。使用这个系统，我已经识别了一部小说 控制有丝分裂表皮干细胞中极性蛋白质空间分布的机制。 在有丝分裂过程中，极性蛋白从质膜内化到细胞膜。 在细胞质分裂过程中，小泡被运回质膜，并以极化的方式重新定位。 这一机制对于适当地维持整个表皮的组织范围的极性是必不可少的。这个 这项提议的独立/Roo阶段的中心目标是破译调节细胞的机制 细胞有丝分裂时的极性，以及这些途径的失调如何影响组织结构， 增殖分化。具体地说，我将1)阐明控制机制。内化 2)发现与细胞分裂过程中维持极性有关的新基因。 有丝分裂；以及3)确定有丝分裂后的子细胞如何重新建立极性。破译 调节增殖性表皮干细胞极性的机制将对 了解极性维持缺陷如何导致人类疾病的长期目标。

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.