Thyroid hormone control of a gene expression network

甲状腺激素对基因表达网络的控制

• 批准号: 7339686
• 负责人: JOHN DAVID FURLOW
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339686
• 关键词: Address; Adult; Amphibia; Animals; Binding; Biological Metamorphosis; Biological Models; Brain; Brain region; Cartilage; Cell Line; Cell Proliferation; Cells; Cessation of life; Chimeric Proteins; Chromatin; Competence; Complex; Coupled; Detection; Development; Dominant-Negative Mutation; Equilibrium; Estrogen Receptor Modulators; Event; Family; Fertilization; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Hormonal; Hormone Responsive; Hormones; Human; In Vitro; Jaw; Length; Life; Ligands; Mammals; Mediating; Modeling; Molecular; Molecular Analysis; Nature; Neurons; Nuclear Receptors; Numbers; Pattern; Phenotype; Proliferating; Promoter Regions; Proteins; RNA Polymerase II; Rana; Range; Receptor Signaling; Recruitment Activity; Relative (related person); Reporter; Reporter Genes; Repression; Role; Specificity; Structure; System; TRAP Complex; Tadpoles; Tamoxifen; Technology; Testing; Thyroid Hormone Receptor; Thyroid Hormone Receptor Gene; Thyroid Hormones; Time; Tissues; Transfection; Transgenic Organisms; Vertebrates; Xenopus; Xenopus laevis; base; cartilage development; hormone response element; human RIPK1 protein; in vivo; interest; knockout gene; new growth; programs; promoter; receptor; receptor expression; receptor function; research study; response; tool

DESCRIPTION (provided by applicant): An important model system for understanding nuclear receptor signaling during development is metamorphosis of the frog Xenopus laevis. Thyroid hormone induces remarkable functional and morphogenetic changes as the larval tadpole transitions into the adult frog. A great deal of progress has been made on the molecular mechanisms of thyroid hormone receptor function in all vertebrates. Besides characterization of the highly conserved thyroid hormone receptor genes themselves, several receptor interacting proteins have been identified that mediate their ability to repress or activate transcription in the absence or presence of ligand, respectively. These coactivators and corepressors, collectively termed coregulators, recruit complexes that modify target gene chromatin or modulate RNA polymerase II access to hormone responsive promoters. Differential expression and/or activity of coregulator complexes have been suggested to influence cell and promoter specific responses to a given hormone, but these experiments have mostly relied on transient transfection and in vitro transcription systems or gene knockout technologies that deprive the animal of these genes from fertilization onward. Our central hypothesis is that the balance of ligand-dependent coactivation and ligand-independent corepression is critical for proper temporal and spatial responses to thyroid hormone during metamorphosis. To test this hypothesis, we will develop transgenic tadpoles that allow us to determine the precise pattern of thyroid hormone receptor mediated transcription in living tadpoles. We will then correlate coactivator and corepressor gene expression with the onset of developmental competence to respond to natural and synthetic Iigands and the tissue specificity of those responses. The relative importance of corepressor and coactivator interactions with the thyroid hormone receptor in vivo will then be tested by two strategies: first, by treatment with NH-3, a compound that disrupts both coactivator and corepressor interaction with the thyroid hormone receptor; and second, by tissue specific and inducible expression of full-length and dominant negative corepressor proteins. Finally, we will analyze gene expression networks regulated by TH in proliferating regions of the brain and jaw cartilage. We are particularly interested in determining the molecular basis for the selective agonism of NH-3 on neuronal versus cartilage proliferation. This selective agonism/antagonism is a common feature of estrogen receptor modulators such as tamoxifen but has not been previously described for thyroid hormone receptors. These last studies will provide new information on gene expression cascades leading to cellular proliferation in two tissues that are dependent on TH for proper development in both amphibians and mammals, including humans. In summary, Xenopus laevis metamorphosis is a powerful model for determining the role of thyroid hormone receptors and their coregulators in tissue specific control of gene expression networks during vertebrate development.

描述（由申请人提供）：用于理解发育过程中核受体信号传导的一个重要模型系统是非洲爪蟾的变态。当幼虫蝌蚪转变为成年青蛙时，甲状腺激素会引起显着的功能和形态发生变化。所有脊椎动物甲状腺激素受体功能的分子机制已取得很大进展。除了高度保守的甲状腺激素受体基因本身的特征之外，还鉴定了几种受体相互作用蛋白，它们分别在配体不存在或存在的情况下介导其抑制或激活转录的能力。这些共激活子和共阻遏物统称为共调节子，它们募集复合物来修饰靶基因染色质或调节 RNA 聚合酶 II 与激素响应启动子的接触。共调节复合物的差异表达和/或活性被认为会影响细胞和启动子对给定激素的特异性反应，但这些实验主要依赖于瞬时转染和体外转录系统或基因敲除技术，这些技术从受精开始就剥夺了动物的这些基因。我们的中心假设是，配体依赖性共激活和配体独立的共抑制的平衡对于变态过程中甲状腺激素的适当时间和空间反应至关重要。为了检验这一假设，我们将开发转基因蝌蚪，使我们能够确定活体蝌蚪中甲状腺激素受体介导的转录的精确模式。然后，我们将把共激活子和辅阻遏物基因表达与对天然和合成配体做出反应的发育能力的开始以及这些反应的组织特异性联系起来。然后，将通过两种策略来测试体内辅抑制因子和辅抑制因子与甲状腺激素受体相互作用的相对重要性：首先，用NH-3治疗，NH-3是一种破坏辅激活因子和辅抑制因子与甲状腺激素受体相互作用的化合物；其次，通过全长和显性负阻遏蛋白的组织特异性和诱导性表达。最后，我们将分析大脑和颌软骨增殖区域中 TH 调节的基因表达网络。我们特别感兴趣的是确定 NH-3 对神经元增殖和软骨增殖选择性激动的分子基础。这种选择性激动/拮抗作用是雌激素受体调节剂（例如他莫昔芬）的共同特征，但之前尚未针对甲状腺激素受体进行描述。最后的这些研究将提供关于导致两栖动物和哺乳动物（包括人类）的两个组织中细胞增殖的基因表达级联的新信息，这两种组织依赖于 TH 来正常发育。总之，非洲爪蟾变态是确定甲状腺激素受体及其共调节因子在脊椎动物发育过程中基因表达网络的组织特异性控制中的作用的强大模型。

项目成果

Measurement of the filtration coefficient (Kfc) in the lung of Gallus domesticus and the effects of increased microvascular permeability.

鸡肺过滤系数 (Kfc) 的测量以及微血管通透性增加的影响。

• DOI: 10.1007/s00360-006-0079-6
• 发表时间: 2006
• 期刊: Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
• 作者: Weidner,WJeffrey;Waddell,DavidS;Furlow,JDavid
• 通讯作者: Furlow,JDavid

Ribozyme suppression of endogenous thyroid hormone receptor activity in Xenopus laevis cells.

核酶抑制非洲爪蟾细胞内源性甲状腺激素受体活性。

• DOI: 10.1093/nar/gkf461
• 发表时间: 2002
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Lim,Wayland;Furlow,JDavid
• 通讯作者: Furlow,JDavid