PIGMENTARY MODEL FOR THYROID HORMONE ACTIONS ON STEM CELL LINEAGES

甲状腺激素对干细胞谱系作用的色素模型

• 批准号: 8914645
• 负责人: DAVID M PARICHY
• 金额: $ 32.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914645
• 关键词: Adolescent; Adult; Affect; Aging; Behavior; Biology; Cell Cycle; Cell Lineage; Cells; Clinical; Competence; Defect; Degenerative Disorder; Dependency; Development; Disease; Embryonic Development; Endocrine; Event; Future; General Population; Genetic Transcription; Genomic approach; Genomics; Health; Homeostasis; Hormonal; Hormones; Human; Human Development; Hypothyroidism; Hypoxia Inducible Factor; Image; Infertility; Injury; Interruption; Lead; Ligands; Macrophage Colony-Stimulating Factor Receptor; Malignant Neoplasms; Mammals; Maps; Mediating; Medicine; Melanophores; Modeling; Molecular; Molecular Genetics; Morphogenesis; Neonatal; Neoplasms; Neural Crest; Oranges; Pathway interactions; Patients; Peripheral Nervous System Diseases; Phenotype; Pigmentation physiologic function; Pigments; Play; Predisposition; Psyche structure; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Regulation; Research; Resolution; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Staging; Stem Cell Development; Stem cells; Sterile coverings; System; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Time; Transgenic Organisms; Work; Zebrafish; adult stem cell; base; cancer prevention; cancer therapy; cell fate specification; combat; embryonic stem cell; fetal; genetic analysis; genetic approach; hypoxia inducible factor 1; innovation; insight; melanocyte; melanoma; migration; molecular marker; mutant; novel; prevent; progenitor; receptor; regenerative; research study; self-renewal; stem; therapy development; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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 degenerative disease. Important to many stem cell systems are interactions with endocrine factors, for regulating cell cycling, fate-specification 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 zebrafish adult pigmentation as an innovative and tractable system for elucidating TH functions in differentiation and morphogenesis as well as homeostasis and neoplasia. Adult pigment cells of zebrafish arise from neural crest-derived latent stem or progenitor cells that differentiate during the larval-to-adult transformation, a period that shares similarities 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 specifies alternative fates or promotes terminal differentiation within defined 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 significantly more prevalent in human melanoma patients 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 mechanisms 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, manipulation of TH status using a conditional transgenic line and lineage-specific 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.

描述（由申请人提供）：干细胞在发育和体内平衡中具有关键作用;了解其生物学对于再生医学、预防和治疗癌症以及开发对抗衰老和退行性疾病的疗法至关重要。对许多干细胞系统来说重要的是与内分泌因子的相互作用，用于调节细胞周期、命运特化或分化。一个这样的因素是甲状腺激素（TH），它在干细胞谱系中具有不同的且通常相反的作用，并且信号传导的缺陷导致精神和身体发育迟缓，周围神经病变，不孕症和其他疾病。这些研究使用斑马鱼成体色素作为一种创新的和易处理的系统，用于阐明TH在分化和形态发生以及稳态和肿瘤形成中的功能。斑马鱼的成体色素细胞来源于神经嵴来源的潜伏干细胞或祖细胞，这些干细胞或祖细胞在幼体向成体转化期间分化， 与哺乳动物的晚期胎儿、新生儿和青少年阶段相似。初步分析表明，TH抑制黑色黑素细胞的发展，同源的哺乳动物黑素细胞，但促进黄色/橙子xanthophores的发展。目标1中的研究将揭示这些效应的细胞基础，重点是TH是否指定替代命运或促进限定祖细胞谱系内的终末分化，以及TH是否调节增殖、迁移或存活的形态发生行为。额外的分析将测试这些谱系的后期TH依赖性稳态以及TH是否防止黑色素瘤发作或进展，因为甲状腺功能减退症在人类黑色素瘤患者中比在一般人群中显著更普遍。目标2中的研究将通过测试经典（“基因组”）信号传导和非经典机制的作用来阐明色素干细胞谱系中TH活性的分子机制，在经典（“基因组”）信号传导中，配体TH受体直接调节靶基因转录，在非经典机制中，TH促进细胞骨架变化并与各种信号传导途径相互作用。额外的分析将测试两种分子机制，这两种机制是介导TH对色素细胞作用的优秀候选者，通过缺氧诱导因子1或通过受体酪氨酸激酶试剂盒和集落刺激因子-1受体的信号传导。目标1和2中的实验将采用一套创新的方法，包括新突变体的遗传分析、使用条件转基因系和谱系特异性转基因效应子操纵TH状态、单细胞命运作图和高分辨率延时成像。总之，这些研究将回答有关色素沉着中TH活性的几个最重要的问题，同时建立一个高度可及的系统，更普遍地在干细胞中分配TH功能。