Regulation of Cell Polarity During Epidermal Growth and Homeostasis

表皮生长和稳态过程中细胞极性的调节

• 批准号: 8325039
• 负责人: Danelle N Devenport
• 金额: $ 24.9万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325039
• 关键词: Address; Adult; Affect; Anterior; Apical; Architecture; Award; Back; Biochemical; Cell Cycle; Cell Polarity; Cell division; Cell membrane; Cells; Communication; Congenital Heart Defects; Cues; Cystic Kidney Diseases; Cytokinesis; Cytoskeleton; Data; Defect; Development; Endocytosis; Ensure; Epidermis; Epithelial; Epithelium; Genes; Genetic; Growth; Hair follicle structure; Homeostasis; Image; In Vitro; Inherited; Instruction; Intercellular Junctions; Interphase Cell; Labyrinth; Lead; Maintenance; Malignant Neoplasms; Membrane; Mentors; Minor; Mitosis; Mitotic; Natural regeneration; Nature; Neural Tube Defects; Organelles; Pathway interactions; Pattern; Phase; Post-Translational Protein Processing; Proteins; RNA Interference; Regulation; Shapes; Skin; Spatial Distribution; Stem cells; Structure; System; Tissues; Transgenic Mice; Transport Vesicles; Vesicle; daughter cell; human disease; keratinocyte; mutant; novel; prevent; protein transport; regenerative; repaired; tissue regeneration; transmission process; tumorigenesis

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.

该提案的长期目标是了解调节细胞极性的机制 表皮生长和再生。细胞极性是指细胞 - 细胞连接不平等的分布， 细胞内的细胞骨架结构和细胞器，是最基本的建筑特征 上皮组织。当细胞极性遭到损害时，细胞变得异常形状，不良导向，并且 不当分层，导致对扩散，分化和肿瘤发生的异常控制。在高度 再生成人上皮组织，例如皮肤，干细胞的失调被认为是一种 上皮癌的根本原因，因此保持细胞极性和组织结构至关重要 随着皮肤细胞不断分裂，分化和死亡。而细胞极性的建立相当不错 理解，对组织再生过程中如何调节极性的知之甚少。因为 哺乳动物皮肤是自然界中最明显的两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，我已经确定了一本小说 控制有丝分裂的表皮干细胞中极性蛋白空间分布的机制。 在有丝分裂期间，极性蛋白从质膜内部化为细胞质膜 囊泡，在细胞因子过程中转回质膜，并以极化方式重新定位。 这种机制对于在表皮上正确维持整个组织的极性至关重要。这 该提案的独立/ROO阶段的核心目的是破译调节细胞的机制 极性作为细胞经历有丝分裂以及这些途径失调如何影响组织结构， 增殖和分化。具体而言，我将1）阐明控制机制。 细胞分裂过程中极性蛋白的； 2）确定对维持极性维持必不可少的新型基因 有丝分裂； 3）定义如何在有丝分裂后子细胞中重新建立极性。解密 调节增生表皮干细胞极性的机制对 理解极性维持缺陷如何导致人类疾病的长期目标。