DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

成人表型的发育起源和稳态机制

• 批准号: 9615510
• 负责人: DAVID M PARICHY
• 金额: $ 47.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9615510
• 关键词: DEVELOPMENTAL; ORIGINS; HOMEOSTATIC; MECHANISMS; UNDERLYING

PROJECT SUMMARY Mechanisms underlying the origin and maintenance of adult form, and naturally occurring variation in adult form, remain poorly understood. The research program described here seeks to elucidate how gene activities are translated through cellular behaviors into specific morphological outcomes at adult stages. Such knowl- edge will provide insights into essential aspects of post-embryonic patterning and morphogenesis. It will also have impacts relevant to human health in the realms of congenital deformity, aging, cancer and regenerative medicine. This program focuses on adult pigmentation of zebrafish and its relatives. Pigment cell lineages in vertebrates originate in the embryonic neural crest and depend on precise mechanisms to segregate fate and regulate differentiation in a context of extensive morphogenesis, and particularly migration. Besides sharing these features with other neural crest derivatives, adult pigment cells are interesting because they organize into a diverse array of naturally occurring patterns; because they arise from latent progenitors—and so can provide insights into stem cells biology more generally; and because these lineages give rise to melanoma, representing a profound failure of adult homeostasis and growth control with deadly consequences. The work proposed here will build on our prior efforts that identified distinct lineages of pigment cells having distinct ge- netic and endocrine requirements, as well as our discovery of several types of interactions among pigment cell classes that are needed to establish, implement, and maintain species-specific forms of adult pattern. Our goals in the coming years are to elucidate: (i) genetic and cellular mechanisms of pigment cell interactions and differential dependencies on thyroid hormone during adult stripe development in zebrafish; (ii) the ways in which pigment cell lineages, and particularly latent stem cells, are regulated during adult homeostasis, and how defects in these processes contribute to melanoma susceptibility and progression; and (iii) how previously unstudied pigment cell fates are regulated, and pigment cells organized, to generate species-specific pattern variants. Towards these ends we will use a suite of approaches, including state of the art imaging and modern methods of interrogating gene activities, and we will exploit not only stripes of zebrafish but also the pattern diversity of close zebrafish relatives, to which the same methods are readily applied. Together our efforts will provide novel insights into the genetic and cellular bases for adult forms of this neural crest derived trait, with implications both basic and translational. !1

项目概要 成人形态起源和维持的机制，以及成人自然发生的变异 形式，仍知之甚少。这里描述的研究计划旨在阐明基因活动如何 通过细胞行为转化为成年阶段的特定形态结果。这样的知识 Edge 将提供对胚胎后模式和形态发生的基本方面的见解。它还将 在先天畸形、衰老、癌症和再生领域对人类健康产生影响 药品。该计划重点研究斑马鱼及其近缘种的成年色素沉着。色素细胞谱系 脊椎动物起源于胚胎神经嵴，并依赖于精确的机制来分离命运和 在广泛的形态发生的背景下调节分化，特别是迁移。除了分享之外 这些特征与其他神经嵴衍生物一样，成体色素细胞很有趣，因为它们组织 形成各种自然发生的模式；因为它们来自潜在的祖先——因此可以 提供更广泛的干细胞生物学见解；因为这些谱系会产生黑色素瘤 代表成人体内平衡和生长控制的严重失败，并带来致命的后果。工作 这里提出的建议将建立在我们之前的努力的基础上，这些努力鉴定了具有不同基因的色素细胞的不同谱系。 遗传和内分泌需求，以及我们发现色素细胞之间几种类型的相互作用 建立、实施和维持物种特定形式的成体模式所需的类。我们的 未来几年的目标是阐明：（i）色素细胞相互作用的遗传和细胞机制以及 斑马鱼成年条纹发育过程中对甲状腺激素的不同依赖性； (二) 方法 哪些色素细胞谱系，特别是潜伏干细胞，在成体稳态过程中受到调节，以及 这些过程中的缺陷如何导致黑色素瘤的易感性和进展； (iii) 之前如何 未经研究的色素细胞命运受到调节，色素细胞被组织起来，以产生物种特异性模式 变种。为了实现这些目标，我们将使用一套方法，包括最先进的成像和现代技术 研究基因活性的方法，我们不仅会利用斑马鱼的条纹，还会利用图案 斑马鱼近亲的多样性，可以很容易地应用相同的方法。我们的共同努力将 为这种神经嵴衍生性状的成人形式的遗传和细胞基础提供了新的见解， 具有基本意义和转化意义。 !1