Inductive properties of the dermal papilla of the hair follicle

描述(申请人提供)：皮肤附属物，毛囊和汗腺，经历了戏剧性的变化，因为人类从灵长类祖先进化而来。对遗传差异的分析揭示了在人类群体中调节皮肤附属物发育的基因的持续选择。这一补充应用的父母拨款旨在识别介导诱导信号的基因，以启动毛囊发育并引导小鼠的形态发生。这项拟议的研究从两个方面扩展了这一分析。首先，在东亚人和美洲原住民中，已经选择了外营养不良蛋白受体中特定的氨基酸替代，这是对头发和汗腺发育都很重要的信号通路的一个组成部分。在与鉴定该等位基因的系统生物学家的合作下，我们创建了衍生的人类等位基因的小鼠模型，并将研究其在小鼠中的功能。第二个目标是使用系统生物学方法来识别调节小鼠毛囊和汗腺密度的基因，并确定调节这两个附件密度的机制是否存在错综复杂的联系。这个由系统生物学家组成的基本团队研究人类基因组中最近的选择特征，是分析基因在小鼠皮肤附肢发育中的作用的专家，并由一名皮肤附属物在早期人类进化中的作用专家和发育生物学中使用比较方法的领导者组成。有了这个跨学科的研究团队，我们将父母拨款中的分析扩展到另一种皮肤附属物--外分泌汗腺，应用由我们的合作者的专业知识实现的新方法，并将我们在老鼠身上的分析集中在对人类皮肤附属物分歧最重要的基因上。这项工作的成功完成将应用于改善伤口愈合和皮肤移植，以及了解和治疗皮肤附件疾病，包括脱水/缺水外胚层发育不良和脱发。这也将有助于我们理解人类群体中的遗传变异如何有助于不同群体中皮肤及其附件的独特属性。 与公共卫生相关：与其他哺乳动物相比，人类体毛稀少，汗腺密度高。本研究旨在了解毛囊和汗腺形成的遗传规律，以及这两个独立的微小器官变化的联系方式。新发现的调节这些器官形成的基因变体将在小鼠身上进行功能测试，并将在不同的人类群体中进行丰富，基因组分析方法将被应用于识别调节小鼠毛囊和汗腺相对密度急剧变化的基因。这将指导我们对人类遗传变异的分析，这些变异可能会影响独特的头发和汗腺生物学。

DESCRIPTION (provided by applicant): Cutaneous appendages, the hair follicles and sweat glands, underwent dramatic change as humans evolved from primate ancestors. Analyses of genetic divergence reveal ongoing selection on genes that regulate cutaneous appendage development within human populations. The parent grant for this supplemental application is designed to identify genes that mediate inductive signaling to initiate hair follicle development and guide morphogenesis in the mouse. The proposed research extends that analysis in two ways. First, a specific amino acid substitution in the Ectodysplasin receptor, a component of a signaling pathway important for both hair and sweat gland development, has been selected for in East Asians and Native Americans. In collaboration with the systems biologist that identified this allele, we created a mouse model of the derived human allele and will study its function in the mouse. The second goal uses systems biology approaches to identify genes that regulate the density of hair follicles and sweat glands in the mouse, and to determine if mechanisms that regulate the densities of these two appendages are intricately linked. This basic team of systems biologists studying signatures of recent selection within the human genome and an expert in analyzing the role of genes in cutaneous appendage development in mice is augmented by an expert on the role of cutaneous appendages in early human evolution and a leader in the use of comparative approaches in developmental biology. With this interdisciplinary research team we extend the analysis in the parent grant to an additional cutaneous appendage, the eccrine sweat gland, apply new approaches made possible by the expertise of our collaborators, and focus our analysis in the mouse on the genes most important for human cutaneous appendage divergence. The successful completion of this work will have application in improved wound healing and skin grafts, and in the understanding and treatment of disorders of cutaneous appendages including anhydrotic/hypohydrotic ectodermal dysplasias and alopecias. It will also contribute to our understanding of how genetic variation within the human population contributes to unique properties of the skin and its appendages in different populations. PUBLIC HEALTH RELEVANCE: Humans have sparse body hair and high densities of sweat glands compared to other mammals. This research is designed to understand the genetic regulation of hair follicle and sweat gland formation and the way that the changes of these two independent mini-organs are linked. The function of newly discovered variants of genes that regulate the formation of these organs and are enriched in different human populations will be tested in mice, and the approaches of genome analysis will be applied to identify genes that regulate a dramatic shift in the relative density of hair follicles and sweat glands in mice. This will guide our analysis of genetic variation in humans that may affect distinctive hair and sweat gland biology.