Thyroid hormone receptors and development

甲状腺激素受体和发育

基本信息

批准号：
7593616
负责人：
Douglas Forrest
金额：
$ 34.99万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7593616
关键词：
Adult Anterior Pituitary Gland Binding Biological Biological Models Biological Process Cells Chromatin Structure Chromosomes, Human, Pair 14 Chromosomes, Human, Pair 3 Cochlea Collaborations Color Visions Complex DNA Development Endocrine Event Functional RNA Gene Expression Genes Genetic Genomics Hearing Homeostasis Hormones Human Hypothalamic structure In Vitro Individual Introns Investigation Ligands Location Maps Mediating Mus National Institute of Diabetes and Digestive and Kidney Diseases Nature Opsin Patients Pattern Photoreceptors Pituitary Gland Positioning Attribute Promoter Regions Protein Isoforms Range Receptor Gene Regulatory Element Resistance Retina Retinal Retinal Cone Role Sampling Series Structure System THRB gene Thinking Thyroid Hormone Receptor Thyroid Hormones Time Tissues body system comparative human disease in vivo liver function mouse model novel pituitary thyroid axis promoter receptor response transcription factor

项目摘要

Thyroid hormone mediates a remarkable range of functions in many tissues and organ systems. These functions are important both in development and adult homeostasis. The breadth of responses raises a key question concerning the mechanisms that determine the nature, time and place of a given response to thyroid hormone. How does one hormone elicit so many different responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that produce the cellular response. Two receptor genes, Thrb and Thra, encode several TR isoforms that are expressed in different developmental and tissue-specific patterns. Thus, the ability to express a given receptor isoform in a particular tissue provides a means of conferring a specific biological response. This project investigates the mechanisms that direct the unique expression patterns of the TRb isoforms encoded by the Thrb gene as a mechanism that determines specific functions of thyroid hormone. Progress: 1. The Thrb gene has an unusually large and complex structure, spanning about 400 kb on human chromosome 3 or mouse chromosome 14. A detailed mapping study in mouse model strains, has identified control regions of the mouse Thrb gene that direct tissue-specific expression of the TRb2 isoform in pituitary, cochlea and retina. This highly specialized control region of genomic DNA lies in a non-coding, intron region of the gene. The unusual location and multi-functional nature of the control region provides a model system of biological importance in which to investigate the transcriptional mechanisms that regulate chromatin structure and gene activity in different tissues. 2. To investigate the significance of these chromosomal control regions in humans, the intron and promoter regions of the mouse Thrb gene have been compared with the corresponding regions of the human THRB gene. The potential role of polymorphic changes in these sequences in the human disease of resistance to thyroid hormone is being investigated in a series of DNA samples from patients (collaboration with Dr F. Celi, NIDDK).

甲状腺激素在许多组织和器官系统中介导了显着的功能。这些功能在发展和成人稳态中都很重要。反应的广度提出了一个关键问题，该问题是关于决定甲状腺激素的性质，时间和地点的机制。一种激素如何引起这么多不同的反应？甲状腺激素受体（TR）充当配体调节的转录因子，并在产生细胞反应的事件链中占据关键位置。两个受体基因THRB和THA编码以不同发育和组织特异性模式表达的几种TR同工型。因此，在特定组织中表达给定受体同工型的能力提供了一种赋予特定生物学反应的方法。该项目研究了指导由THRB基因编码的TRB同工型的独特表达模式的机制，作为确定甲状腺激素特定功能的机制。进步： 1。THRB基因具有异常大且复杂的结构，在人类3或小鼠染色体14上涵盖了约400 kb。小鼠模型菌株中的详细映射研究鉴定了小鼠THRB基因的对照区域，该控制区域可直接导致垂体，同伴和视网膜和视网膜和视网膜中TRB2同工型的组织特异性表达。这种高度专业的基因组DNA控制区域在于基因的非编码，内含子区域。控制区域的异常位置和多功能性质提供了一种生物学重要性的模型系统，在该模型中，研究了调节不同组织中染色质结构和基因活性的转录机制。 2。为了研究这些染色体对照区域对人类的重要性，将小鼠THRB基因的内含子和启动子区域与人类THRB基因的相应区域进行了比较。在来自患者的一系列DNA样本中，正在研究这些序列中多态性变化在对甲状腺激素抗性的人类疾病中的潜在作用（与F. Celi博士合作，NIDDK）。