PIGMENTARY MODEL FOR THYROID HORMONE ACTIONS ON STEM CELL LINEAGES

项目摘要/摘要 干细胞在发育和动态平衡中起着至关重要的作用；了解它们的生物学特性对于重新认识它们是至关重要的。 生殖医学，预防和治疗癌症，以及开发抗击衰老和退化的疗法- 传播性疾病。对许多干细胞系统来说，重要的是与内分泌因子相互作用，以调节细胞 骑自行车，命运使然阳离子或分化。其中一个因素是甲状腺激素(TH)，它有多种不同的 通常在干细胞谱系中产生相反的影响，信号缺陷会导致精神和身体上的障碍 发育迟缓、周围神经病、不孕不育等疾病。这些研究使用斑马他是成年猪仔- TATION作为一种创新和易操作的系统来阐明TH在分化和形态发生中的功能 以及动态平衡和肿瘤。斑马成体色素细胞自发性高血压由神经脊源性潜伏期引起 在幼虫到成虫的转化过程中分化的干细胞或祖细胞，这一时期分享了类似的- 与哺乳动物的胎儿、新生儿和青春期晚期有关。初步分析表明， 抑制与哺乳动物黑素细胞同源的黑色黑素载体的发展，但促进 黄色/橙色黄色团的发展。目标1的研究将揭示这些效应的细胞基础， 重点关注这些产品是否ES的另一种命运或促进DE内的末端分化NED先祖 血统，以及TH是否调节增殖、迁移或生存的形态发生行为。其他内容 分析将测试这些血统后来依赖TH的动态平衡，以及TH是否保护 以甲状腺功能减退为标志的黑色素瘤的发病或进展在人类黑色素瘤患者中更为常见- 比一般人群中的发病率要高。AIM 2的研究将阐明TH活性的分子机制 通过测试连接TH受体的规范(基因组)信号的作用而形成色素干细胞谱系 直接调控靶基因转录，以及TH促进细胞骨架的非规范机制 改变多种信号通路并与之相互作用。其他分析将测试两种分子机制- NISM是通过低氧诱导因子1�介导色素细胞TH效应的优秀候选基因 或通过受体酪氨酸激酶试剂盒和集落刺激因子-1受体进行信号传递。实验在 AIMS 1和AIMS 2将采用一套创新的方法，包括对新突变的遗传分析，MA- 利用有条件转基因品系和谱系物种获得TH状态C转基因效应器，单细胞- 命运测绘和高分辨率时间推移成像。总而言之，这些研究将回答几个最重要的问题 在建立一个高度可用的广告系统时，关于色素沉着中TH活性的重要问题 更广泛地说，涂抹TH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.