Investigating the role of cell competition in epidermal development

项目总结： 皮肤形成一种基本的渗透性屏障，保护内部器官和组织免受 损伤、脱水、病原体入侵和其他有害的环境应激。缺陷屏障功能 与广泛的病理有关，包括慢性伤口，先天性疾病，上皮 癌症、感染和其他炎症性疾病。为了了解这些疾病状态的基础， 首先了解表皮在发育过程中形成的过程是至关重要的。 皮肤由单层干细胞前体细胞发育而成，在功能上特化、多层 在出生时，渗透性屏障通过快速扩张和分化的过程。质量控制是什么？ 确保组织功能的机制在发育过程中得到优化，为产后做准备 生活？一种称为细胞竞争的现象被提出作为一种快速的选择机制 扩张的组织，不太适合的“失败者”细胞被更适合的邻近“赢家”细胞淘汰。广度 目前尚不清楚细胞竞争对组织和器官生长起到保守的调节作用。这项研究设定了 来检验这一假设，即在哺乳动物的皮肤中，细胞竞争提供了基本的质量控制 在发育过程中保护组织免受出生前和出生后生活压力的机制。 利用老鼠身上可获得的一种独特的遗传工具组合，拟议中的工作采用了一种组合 细胞生物学、谱系追踪和计算方法，以揭示细胞竞争的证据 表皮发育(目标1)。此外，建立在新建立的系统的基础上，在实验上诱导 细胞竞争、功能遗传学和定量活体成像将被用来剖析遗传规律 细胞竞争(目标2)。最后，使用功能分析，建议的实验检查 在发育过程中破坏细胞竞争对皮肤执行其功能的影响 基本屏障功能(目标3)。预期结果将：(A)建立一种新的范式，并产生 研究哺乳动物细胞竞争的工具；(B)为早期的时空控制提供新的视角 (C)阐明了细胞竞争的分子基础，这可能是 长期用于治疗多种屏障病变。在…的监督下 领先的表皮细胞生物学家Elaine Fuchs博士，细胞竞争专家Laura博士的共同导师 约翰斯顿，以及洛克菲勒大学激动人心的训练环境，我的理想位置是完全 发展我的技术技能、知识和领导力。我的研究、培训和职业发展将 请允许我在表皮和发育生物学领域建立一个独特的研究利基市场 调查员。

PROJECT SUMMARY: The skin forms an essential permeability barrier that protects internal organs and tissues from physical damage, dehydration, pathogen invasion, and other harmful environmental stresses. Defective barrier function is associated with a broad range of pathologies including chronic wounds, congenital diseases, epithelial cancers, infection, and other inflammatory conditions. In order to understand the basis of these disease states, it is vital to first understand the processes by which the epidermis forms during development. The skin arises from a single layer of stem cell progenitors to become a functionally specialized, multi-layered permeability barrier at birth via a process of rapid expansion and differentiation. What are the quality control mechanisms that act to ensure tissue function is optimized during development in preparation for post-natal life? A phenomenon known as cell competition has been proposed to act as a selection mechanism in rapidly expanding tissues, whereby less fit “loser” cells are eliminated by fitter neighbouring “winner” cells. The extent to which cell competition acts as a conserved regulator of tissue and organ growth is unknown. This study sets out to test the hypothesis that in the mammalian skin, cell competition provides an essential quality control mechanism during development to safeguard the tissue against stresses in both pre- and post-natal life. Using a unique combination of genetic tools available in the mouse, the proposed work employs a combination of cell biology, lineage tracing and computational approaches to uncover evidence for cell competition during epidermal development (Aim 1). Furthermore, building on a newly established system to experimentally induce cell competition, functional genetics and quantitative live imaging will be used to dissect the genetic regulation of cell competition (Aim 2). Finally, using functional assays, the proposed experiments examine the consequence of disrupting cell competition during development on the ability of the skin to carry out its essential barrier function (Aim 3). The expected results will (a) establish a new paradigm and generate genetic tools to study mammalian cell competition; (b) offer new perspective on spatiotemporal control of early epidermal development; (c) shed light on the molecular underpinnings of cell competition, which may be exploited therapeutically in the long term to treat a broad range of barrier pathologies. Under the supervision of leading epidermal cell biologist, Dr. Elaine Fuchs, the co-mentorship of cell competition expert, Dr. Laura Johnston, and the stimulating training environment at the Rockefeller University, I am ideally positioned to fully develop my technical skills, knowledge, and leadership. My research, training, and career development will allow me to establish a unique research niche in epidermal and developmental biology as an independent investigator.