Tissue-specific functions of thyroid hormone receptors

甲状腺激素受体的组织特异性功能

• 批准号: 10919429
• 负责人: Douglas Forrest
• 金额: $ 115.13万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 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/10919429
• 关键词: Address; Adrenal Cortex; Adrenal Glands; Adult; Age; Aging; Anterior Pituitary Gland; Auditory system; Binding; Binding Sites; Biological Process; Brain; Cell membrane; Cells; Chromatin; Circulation; Clinical; Cochlea; Cre driver; Development; Disease; Endocrine; Endocrine Glands; Endocrine system; Enhancers; Enzymes; Event; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic study; Genomic DNA; Genomic approach; Genomics; Hearing; Homeostasis; Hormones; Human; Infant; Iodide Peroxidase; Kidney; Ligands; Liver; Lung; Mediating; Membrane Transport Proteins; Metabolic; Molecular; Mus; Mutation; Organ; Pattern; Pituitary Gland; Population; Positioning Attribute; Presbycusis; Production; Protein Isoforms; Receptor Gene; Resistance; Retina; Retinal Cone; Role; Sensory; Site; Specificity; Syndrome; System; THRA gene; THRB gene; Testing; Testis; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyrotropin; Tissues; Transcriptional Regulation; cell cortex; cell type; chromatin modification; cochlear development; differential expression; genetic manipulation; novel; pituitary thyroid axis; promoter; receptor; receptor binding; receptor function; response; sexual dimorphism; transcription factor; uptake

Thyroid hormone mediates a remarkable range of actions in many tissues and organs. These actions promote the development of tissues in the fetus and infant and the function of tissues at more mature ages and in adults. The breadth of different responses, including in the nervous, sensory, metabolic and endocrine systems, highlights a key question concerning the mechanisms that determine the tissue-specificity of the functions of thyroid hormone. How does thyroid hormone elicit so many different cellular responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that elicit a cellular response. Two receptor genes, THRB and THRA, encode receptor isoforms that are expressed in different developmental and tissue-specific patterns and mediate diverse tissue functions. This project investigates the mechanisms that determine the tissue-specific functions of the TRb1 and TRb2 receptor isoforms encoded by the THRB gene. The aim is to reveal the developmental and homeostatic functions of these isoforms and of other cooperative factors that modify the activity of the receptors in different tissues. Elucidating these mechanisms that determine tissue-specific responses to thyroid hormone is a prerequisite for understanding the tissue dysfunction that occurs in human thyroid diseases. We take advantage of genetic, genomic and molecular approaches to investigate: 1. Functions of TRb receptors in differentiation and homeostasis. To determine the biological functions of TRb isoforms, we study genetic models in which TRb1 or TRb2 have been deleted. These studies have identified novel, cell-specific expression patterns of TRb1 in the cochlea and endocrine tissues including the anterior pituitary and adrenal cortex. In the auditory system, we found that TRb1 maintains hearing during adulthood and aging. The findings suggest that thyroid hormone may be a factor that counters age-related hearing loss, a widespread condition in human populations. In the adrenal gland, TRb1 is expressed in a previously unrecognized, sexually-dimorphic, cortical cell population and mediates hypertrophic responses, suggesting direct actions for thyroid hormone in adrenal function. 2. Factors that influence TR activity in tissue-specific fashion. We investigate factors including deiodinase enzymes that activate and inactivate thyroid hormone, as well as plasma membrane transporters that mediate the cellular uptake of thyroid hormone from the circulation into specific cells. We found that in several target tissues (e.g., cochlea, pituitary), deiodinase enzymes provide critical control over TR activity. Recent evidence indicates that tissues such as the retina and the testis are subject to control by type 3 deiodinase, an enzyme that degrades hormone thereby constraining the stimulation of the tissue. The findings support the proposal that specific receptor isoforms and deiodinases function in close cooperation in a given tissue to determine the timing of the specific response. We also found that membrane transporters that control the cellular uptake of thyroid hormone are critical for cochlear development and potentially for the development of other tissues. 3. Target genes for TRb isoforms in natural tissues. To study this critical question regarding the mechanisms by which thyroid hormone stimulates cellular differentiation and function, we have derived genetic models to investigate mechanisms of transcriptional regulation by TRb receptors of candidate target genes. These studies involve a range of molecular and genomic approaches, including use of novel genetic models, to identify changes in gene expression patterns and genomic DNA binding sites for these receptor isoforms in different tissues, with a focus on endocrine (pituitary) and sensory (cochlea) systems.

甲状腺激素介导了许多组织和器官中的显着作用。这些作用促进了胎儿和婴儿组织的发展以及在更成熟的年龄和成年人中组织的功能。不同反应的广度，包括在神经，感觉，代谢和内分泌系统中，突出了有关决定甲状腺激素功能组织特异性的机制的关键问题。甲状腺激素如何引起如此多种不同的细胞反应？甲状腺激素受体（TR）充当配体调节的转录因子，并在引起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受体同工型，并介导多种组织功能。该项目研究了确定由THRB基因编码的TRB1和TRB2受体同工型的组织特异性功能的机制。 目的是揭示这些同工型和其他合作因素的发育和稳态功能，这些因素改变了受体在不同组织中的活性。阐明这些确定组织特异性反应对甲状腺激素的机制是理解人甲状腺疾病中发生的组织功能障碍的先决条件。 我们利用遗传，基因组和分子方法进行研究： 1。TRB受体在分化和稳态中的功能。为了确定TRB同工型的生物学功能，我们研究了已删除TRB1或TRB2的遗传模型。这些研究已经确定了TRB1在耳蜗和内分泌组织中的新型细胞特异性表达模式，包括前垂体和肾上腺皮质。在听觉系统中，我们发现TRB1在成年和衰老期间保持听力。研究结果表明，甲状腺激素可能是抵消与年龄相关的听力损失的因素，这是人口中普遍存在的情况。在肾上腺中，TRB1在先前未识别的，性二态，皮质细胞群体中表达，并介导肥大反应，这表明甲状腺激素在肾上腺功能中的直接作用。 2。以组织特异性影响TR活性的因素。我们研究了激活和失活的甲状腺激素的脱碘酶，以及质膜转运蛋白，这些酶从循环中介导甲状腺激素从循环中介导的细胞摄取特定细胞。 我们发现，在几种靶组织（例如耳蜗，垂体）中，脱碘酶对TR活性提供了批判性控制。最近的证据表明，诸如视网膜和睾丸之类的组织受3型去二十二酶的控制，这种酶会降解激素，从而限制组织的刺激。这些发现支持以下建议：特定受体同工型和去二偶氮酶在给定的组织中密切合作，以确定特定响应的时间。 我们还发现，控制甲状腺激素的细胞摄取的膜转运蛋白对于人工耳蜗发育至关重要，并且可能对其他组织的发育有可能。 3。天然组织中TRB同工型的靶基因。为了研究有关甲状腺激素刺激细胞分化和功能的机制的关键问题，我们衍生了遗传模型，以研究候选靶基因的TRB受体转录调控的机制。这些研究涉及一系列分子和基因组方法，包括使用新遗传模型，以确定不同组织中这些受体同工型的基因表达模式的变化和基因组DNA结合位点，重点是内分泌（垂体）和感觉（垂体）和感觉（cochlea）系统。

项目成果

An animal model for Pierpont syndrome: a mouse bearing the Tbl1xr1Y446C/Y446C mutation.

• DOI: 10.1093/hmg/ddac086
• 发表时间: 2022-08-25
• 期刊: Human molecular genetics
• 影响因子: 3.5

The Ins and Outs of Steroid Hormone Transport Across the Plasma Membrane: Insight From an Insect.

类固醇激素跨质膜运输的来龙去脉：来自昆虫的见解。

• DOI: 10.1210/en.2018-01034
• 发表时间: 2019
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Schweizer,Ulrich;Braun,Doreen;Forrest,Douglas
• 通讯作者: Forrest,Douglas

A heartfelt response: new thyroid hormone-sensitive neurons in the hypothalamus.

衷心的回应：下丘脑中新的甲状腺激素敏感神经元。

• DOI: 10.1172/jci67448
• 发表时间: 2013
• 期刊: The Journal of clinical investigation
• 作者: Forrest,Douglas;Wess,Jurgen
• 通讯作者: Wess,Jurgen

Emilin 2 promotes the mechanical gradient of the cochlear basilar membrane and resolution of frequencies in sound.

Emolin 2 促进耳蜗基底膜的机械梯度和声音频率的分辨率。

• DOI: 10.1126/sciadv.aba2634
• 发表时间: 2020
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Russell,IanJ;Lukashkina,VictoriaA;Levic,Snezana;Cho,Young-Wook;Lukashkin,AndreiN;Ng,Lily;Forrest,Douglas
• 通讯作者: Forrest,Douglas

Biphasic expression of thyroid hormone receptor TRβ1 in mammalian retina and anterior ocular tissues.

• DOI: 10.3389/fendo.2023.1174600
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2