Spindle Orientation in Skin Development and Homeostasis

皮肤发育和稳态中的纺锤体方向

• 批准号: 10474961
• 负责人: Terry H Lechler
• 金额: $ 45.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474961
• 关键词: Adult; Affect; Anus; Architecture; Buffers; Cardiac development; Cell Fate Control; Cell division; Cells; Data; Defect; Development; Embryo; Epidermis; Exhibits; Foundations; Funding; Generations; Genital; Genitalia; Goals; Growth; Hair; Hair follicle structure; Head and Neck Squamous Cell Carcinoma; Homeostasis; Human Papillomavirus; In Vitro; Kinesin; Malignant Neoplasms; Microtubules; Mitotic spindle; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Normal tissue morphology; Oncogenes; Oncogenic; Pathogenicity; Physiology; Play; Positioning Attribute; Proteins; Role; Skin; Stratification; Time; Tissues; Viral; Virus; Work; adaptive immune response; base; insight; keratinocyte; mouse model; neurodevelopment; novel; polypeptide; progenitor; response; skin organogenesis; three dimensional structure; tool; tumor; tumor growth

Abstract Cell division orientation must be tightly controlled for the generation of normal tissue architecture and cell fates. In the skin, oriented cell divisions promote the stratification of the embryonic epidermis and morphogenesis of hair follicles. In adults, spindle orientation buffers the epidermis against oncogenic insults and tissue overgrowth. Given these important functions, it is paramount to understand the mechanisms by which mitotic spindles are precisely oriented. While some of the proteins required for spindle orientation have been identified, we do not fully understand how this molecular machinery generates forces on astral microtubules to allow accurate control of cell division orientation. Our preliminary studies have identified novel regulators of epidermal spindle orientation. Here we propose studies to undercover the underlying mechanisms by which these proteins affect division orientation. Further, we will use novel mouse models to define how spindle orientation contributes to hair follicle morphogenesis and adult epidermal homeostasis. Together, these data will provide a deeper mechanistic understanding of spindle orientation which has essential functions in epidermal, cardiac and neural development as well as the adaptive immune response. In addition, this work has direct relevance for understanding how spindle orientation controls cell fates in hair development, and how it acts to suppress tissue overgrowth when homeostasis is perturbed.

摘要 为了产生正常的组织结构和细胞，必须严格控制细胞分裂方向。 命运在皮肤中，定向细胞分裂促进胚胎表皮的分层， 毛囊的形态发生。在成年人中，纺锤体方向缓冲表皮对致癌性损伤 和组织过度生长。考虑到这些重要的功能，通过以下方式了解这些机制至关重要： 有丝分裂纺锤体的精确定位虽然纺锤体定向所需的一些蛋白质 虽然已经被确认，但我们并不完全理解这种分子机制是如何在星体上产生力量的。 微管，以允许精确控制细胞分裂方向。我们的初步研究发现 表皮纺锤体方向的调节因子。在这里，我们提出研究，以掩盖潜在的 这些蛋白质影响分裂方向的机制。此外，我们将使用新的小鼠模型， 定义纺锤体方向如何有助于毛囊形态发生和成人表皮稳态。 总之，这些数据将提供一个更深层次的机械理解主轴方向， 在表皮、心脏和神经发育以及适应性免疫反应中的基本功能。 此外，这项工作对于理解纺锤体方向如何控制毛发中细胞的命运具有直接的相关性 发育，以及当体内平衡被扰乱时它如何抑制组织过度生长。