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: 8740681
• 负责人: DAVID M PARICHY
• 金额: $ 29.41万
• 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/8740681
• 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; Genetic Transcription; Genomics; 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; hypoxia inducible factor 1; innovation; insight; melanocyte; melanoma; migration; molecular marker; mutant; novel; prevent; progenitor; public health relevance; 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(申请人提供)：干细胞在发育和动态平衡中具有关键作用；了解它们的生物学对于再生医学、预防和治疗癌症以及开发抗击衰老和退行性疾病的治疗方法至关重要。对许多干细胞系统来说，重要的是与内分泌因子相互作用，以调节细胞周期、命运指定或分化。其中一个因素是甲状腺激素(TH)，它在干细胞谱系中具有不同的、经常是相反的作用，其信号缺陷会导致智力和身体发育迟缓、周围神经疾病、不孕不育和其他疾病。这些研究使用斑马鱼成体色素沉着作为一种创新和易操作的系统，以阐明TH在分化和形态发生以及动态平衡和肿瘤发生中的功能。斑马鱼的成体色素细胞来自神经脊源性的潜伏干细胞或祖细胞，它们在幼体到成体的转变过程中分化，这一时期 与哺乳动物的胎儿晚期、新生儿和青春期的相似性。初步分析表明，TH抑制了与哺乳动物黑素细胞同源的黑色黑素细胞的发育，但促进了黄色/橙色黄色素细胞的发育。目标1的研究将揭示这些效应的细胞基础，重点是TH是否指定了可供选择的命运或促进了特定祖细胞谱系内的末端分化，以及TH是否调节了增殖、迁移或生存的形态发生行为。其他分析将测试这些血统的TH依赖的动态平衡，以及TH是否能预防黑色素瘤的发生或发展，因为甲状腺功能减退症在人类黑色素瘤患者中明显比普通人群中更普遍。AIM 2中的研究将通过测试连接的TH受体直接调控靶基因转录的典型(“基因组”)信号的作用，以及TH促进细胞骨架变化并与多种信号通路相互作用的非典型机制，来阐明色素干细胞系中TH活性的分子机制。其他分析将测试两种分子机制，它们是通过低氧诱导因子1或通过受体酪氨酸激酶试剂盒和集落刺激因子-1受体信号来调节色素细胞的TH效应。AIMS 1和AIMS 2的实验将采用一套创新的方法，包括对新突变的遗传分析，使用条件转基因品系和特定血统的转基因效应器来操纵TH状态，单细胞命运图，以及高分辨率时间推移成像。总而言之，这些研究将回答关于色素沉着中TH活性的几个最重要的问题，同时建立一个高度可访问的系统，以更广泛地补充干细胞中的TH功能。