PIGMENTARY MODEL FOR THYROID HORMONE ACTIONS ON STEM CELL LINEAGES

项目总结/摘要 干细胞在发育和体内平衡中起着关键作用;了解它们的生物学特性对于重新认识干细胞至关重要。 生殖医学，预防和治疗癌症，以及开发对抗衰老和退化的疗法- 病毒性疾病对于许多干细胞系统来说，重要的是与内分泌因子的相互作用，用于调节细胞增殖， 自行车，特定于命运
或分化。一个这样的因素是甲状腺激素（TH），它具有多样性， 通常在干细胞谱系中起相反的作用，信号传导的缺陷会导致精神和身体上的疾病。 发育迟缓、周围神经病、不育症和其它病症。这些研究使用斑马
sh成年猪， 作为一个创新的和易于处理的系统，用于阐明TH在分化和形态发生中的功能 以及体内平衡和肿瘤形成。斑马成体色素细胞
它起源于神经嵴源性潜伏期 干细胞或祖细胞在幼虫向成虫转化期间分化，这一时期与 与哺乳动物的晚期胎儿、新生儿和青少年阶段有关。初步分析表明， 抑制与哺乳动物黑素细胞同源的黑色黑素细胞的发育，但促进 黄色/橙子黄色素细胞的发育。目标1中的研究将揭示这些效应的细胞基础， 关注TH物种是否
或促进终末分化
ned祖先 谱系，以及TH是否调节增殖、迁移或存活的形态发生行为。额外 分析将测试这些谱系的后期TH依赖性稳态，以及TH是否能防止 黑色素瘤发作或进展，如甲状腺功能减退，
在人类黑色素瘤患者中更为普遍， 比一般人群。目的2的研究将阐明TH活性的分子机制， 通过测试典型的色素干细胞谱系的作用，基因组）信号，其中配体TH受体 直接调节靶基因转录，和非经典机制，其中TH促进细胞骨架 改变并与多种信号通路相互作用。进一步的分析将测试两种分子机制- nisms是通过缺氧诱导因子1介导TH对色素细胞作用的优秀候选者。 或通过受体酪氨酸激酶Kit和集落刺激因子-1受体进行信号传导。实验 目标1和2将采用一套创新的方法，包括新突变体的遗传分析， 利用条件转基因品系和谱系种的TH状态的确定
c转基因效应子，单细胞- 命运绘图和高分辨率延时成像。总之，这些研究将回答几个最重要的问题， 关于TH活动在色素沉着的重要问题，同时建立一个高度可及的系统， 敷料TH更普遍地在干细胞中起作用。

PROJECT SUMMARY/ABSTRACT Stem cells have critical roles in development and homeostasis; understanding their biology is essential for re- generative medicine, preventing and treating cancer, and developing therapies to combat aging and degenera- tive disease. Important to many stem cell systems are interactions with endocrine factors, for regulating cell cycling, fate-speci
cation or differentiation. One such factor is thyroid hormone (TH), which has diverse and often opposing effects across stem cell lineages, and for which defects in signaling lead to mental and physical retardation, peripheral neuropathies, infertility and other disorders. These studies use zebra
sh adult pigmen- tation as an innovative and tractable system for elucidating TH functions in differentiation and morphogenesis as well as homeostasis and neoplasia. Adult pigment cells of zebra
sh arise from neural crest-derived latent stem or progenitor cells that differentiate during the larval-to-adult transformation, a period that shares similari- ties with late fetal, neonatal and adolescent stages of mammals. Preliminary analyses demonstrated that TH represses the development of black melanophores, homologous to mammalian melanocytes, but promotes the development of yellow/orange xanthophores. Studies in Aim 1 will uncover the cellular bases for these effects, focusing on whether TH speci
es alternative fates or promotes terminal differentiation within de
ned progenitor lineages, and whether TH modulates morphogenetic behaviors of proliferation, migration or survival. Additional analyses will test for later TH-dependent homeostasis of these lineages and whether TH protects against melanoma onset or progression, as hypothyroidism is signi
cantly more prevalent in human melanoma pa- tients than in the general population. Studies in Aim 2 will elucidate molecular mechanisms of TH activities in pigment stem cell lineages by testing roles for canonical (genomic) signaling, in which liganded TH receptors directly modulate target gene transcription, and non-canonical mechanisms, in which TH promotes cytoskeletal changes and interacts with a variety of signaling pathways. Additional analyses will test two molecular mecha- nisms that are excellent candidates for mediating TH effects on pigment cells, via hypoxia inducible factor 1� or signaling through the receptor tyrosine kinases Kit and Colony stimulating factor-1 receptor. Experiments in Aims 1 and 2 will employ an innovative suite of approaches including genetic analyses of new mutants, ma- nipulation of TH status using a conditional transgenic line and lineage-speci
c transgenic effectors, single cell- fate mapping, and high-resolution time-lapse imaging. Together, these studies will answer several of the most important questions about TH activities in pigmentation while establishing a highly accessible system for ad- dressing TH functions in stem cells more generally.