Thyrocyte Protein Transport to the Cell Surface

甲状腺细胞蛋白质转运至细胞表面

• 批准号: 8003365
• 负责人: PETER ARVAN
• 金额: $ 7.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-23 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003365
• 关键词: Alleles; Animal Model; Apical; Automobile Driving; Basic Science; Binding; Biological; Blood Circulation; Cell Death; Cell Respiration; Cell surface; Cells; Cholinesterases; Clinical; Complex; Cretinism; Data; Defect; Development; Digestion; Dimerization; Disease; Endocrine; Endocytosis; Endoplasmic Reticulum; Epithelial Cells; Funding; Future; Generations; Genes; Gland; Glycoproteins; Goiter; Grant; Heterodimerization; Homodimerization; Hormones; Human; Hydrogen Peroxide; Hypothyroidism; Intracellular Transport; Iodides; Iodination reaction; Laboratories; Link; Metabolism; Molecular; Molecular Chaperones; Monoiodotyrosine; Mus; Mutation; Pathway interactions; Patients; Peroxidases; Phenotype; Play; Production; Quality Control; Reporting; Research; Role; SM 22 muscle protein; System; Thyroglobulin; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; United States National Institutes of Health; Vertebrates; Work; basolateral membrane; biological adaptation to stress; clinically relevant; clinically significant; deiodination; endoplasmic reticulum stress; hormone biosynthesis; in vivo; insight; intracellular protein transport; monolayer; mutant; pressure; protein transport; public health relevance; research study

DESCRIPTION (provided by applicant): The thyroid gland is part of a critical endocrine circuit that influences development and oxidative metabolism in humans, which is largely conserved amongst the vertebrates. As the basic hormone-forming unit of the gland, each thyroid follicle is comprised of a monolayer of epithelial cells secreting thyroglobulin (Tg) into a central apical cavity (the follicle lumen). Thyrocytes access iodide using an electrochemical gradient at the basolateral membrane to drive intracellular accumulation of iodide with eventual transport apically where, in conjunction with H2O2 generation and peroxidase activity, Tg becomes iodinated to form both iodotyrosines and iodothyronines. Ultimately, endocytosis and proteolytic digestion allows for release of active thyroid hormones to the bloodstream while deiodination of iodotyrosines reclaims iodide for future Tg iodination. This new grant cycle focuses on Tg transport through the secretory pathway. In Tg, simple structural requirements for hormonogenesis are counterbalanced by evolutionary pressures to conserve iodide, which has resulted in a complex secretory glycoprotein. This complexity generates several fundamental questions concerning intracellular protein transport and endoplasmic reticulum (ER) quality control function that link directly to clinical disease. In the overview, our objective in this grant remains to pursue a basic science analysis in order to explain the most clinically relevant phenotypes. Our primary focus in this renewal application centers around the Tg protein and how difficulties in its intracellular transport relate to patients and animal models with thyroid disease including congenital hypothyroidism with and without goiter. Our Specific Aims for the next 5 years are to elucidate the role of the cholinesterase-like (ChEL) domain of Tg in thyroid hormone biosynthesis, and to develop an in vivo paradigm in which to study cell biological defects associated with congenital Tg deficiency. These studies have clinical significance specific to thyroidology while providing more general insight into the basic and clinical problems found in endoplasmic reticulum storage diseases. PUBLIC HEALTH RELEVANCE: The thyroid gland is part of a critical endocrine circuit that influences development and metabolism in humans. To make thyroid hormone, thyroid follicle cells secrete thyroglobulin (Tg) into a central cavity that functions as a storage depot for iodide and for thyroid hormones, because both iodotyrosines and and thyroid hormones are formed and stored within the Tg protein. Iodinated Tg thus serves the dual function of both thyroid hormone reservoir and iodide reservoir for the body. Tg transport through the secretory pathway is required for its iodination and storage of thyroid hormones. One group reports that mutations in the gene encoding Tg are the most common cause of congenital hypothyroidism (other than iodide deficiency which threatens 200 million peple worldwide). Of the Tg mutants characterized to date, all are defective for transport through the secretory pathway, being retained in a compartment known as the endoplasmic reticulum (ER). Our primary focus centers on the Tg protein and its relationship to patients and animal models with thyroid disease including, but not limited to, congenital goiter.

描述（由申请人提供）：甲状腺是关键内分泌电路的一部分，它影响了人类中的发育和氧化代谢，在脊椎动物中，这在很大程度上是保守的。作为腺体的基本激素形成单位，每个甲状腺卵泡由分泌甲状腺球蛋白（TG）的上皮细胞的单层组成，将其分泌到中心的根尖腔（卵泡腔）中。使用基底外侧膜上的电化学梯度进入碘化物，以驱动碘化物的细胞内积累，最终以最终的运输为顶，其中，与H2O2的生成和过氧化物酶活性一起，TG与碘化相结合，形成两种碘托糖苷和碘霉素。最终，内吞作用和蛋白水解消化允许将活性甲状腺激素释放到血液中，而碘酪氨酸的去牙产物则恢复了碘化物，以供将来的TG碘化碘化物。这个新的赠款周期着重于通过分泌途径的TG运输。在TG中，激素发生的简单结构需求与节约碘化物的进化压力相抵消，这导致了复杂的分泌糖蛋白。这种复杂性产生了有关细胞内蛋白质转运和内质网（ER）质量控制功能的几个基本问​​题，这些质量控制功能直接与临床疾病联系起来。在概述中，我们在这笔赠款中的目标仍然是进行基础科学分析，以解释最临床相关的表型。我们在此更新应用中的主要重点围绕TG蛋白以及其细胞内转运的困难与患有甲状腺疾病的患者和动物模型有关，包括先天性甲状腺功能减退症，没有甲状腺肿。我们未来5年的具体目的是阐明TG在甲状腺激素生物合成中的胆碱酯酶样（CHEL）结构域的作用，并开发一种体内范式，在该体内研究与先天性TG缺乏症相关的细胞生物学缺陷。这些研究具有针对甲状腺学特有的临床意义，同时对内质网储存疾病中发现的基本和临床问题提供了更一般的见解。公共卫生相关性：甲状腺是影响人类发展和代谢的关键内分泌电路的一部分。为了制作甲状腺激素，甲状腺卵泡细胞将甲状腺球蛋白（TG）分泌到中央腔中，该腔功能充当碘化物和甲状腺激素的储存库，因为碘诺托糖苷和甲状腺激素均形成并存储在TG蛋白中。因此，碘化的TG具有甲状腺激素储层和碘化物储层的双重功能。通过甲状腺激素的碘化和储存需要TG通过分泌途径的TG运输。一个小组报告说，编码TG的基因突变是先天性甲状腺功能减退症的最常见原因（除了威胁到全球范围内占2亿个peple的碘化物缺乏症之外）。在迄今为止表征的TG突变体中，所有这些都在通过分泌途径的运输中有缺陷，并保留在称为内质网（ER）的隔室中。我们的主要重点是TG蛋白及其与患有甲状腺疾病的患者和动物模型的关系，包括但不限于先天性甲状腺肿。