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CFTR regulation of thyroid transport

CFTR 调节甲状腺转运

基本信息

批准号：
8497251
负责人：
PEYING FONG
金额：
$ 28.5万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8497251
关键词：
Ablation Address Amphibia Animal Model Anions Area Basal metabolic rate Binding Biochemical Biological Biological Models Biotinylation Blood Blood Circulation Blood Pressure Cardiac Cardiovascular Diseases Cardiovascular system Cell model Cells Clinical Co-Immunoprecipitations Collection Cyclic AMP Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Developmental Process Disease End stage renal failure Endocytosis Epithelial Epithelium Family suidae Functional disorder Future Gene Family Goals Health Herpes zoster disease Hormones Human Cloning Hypothyroidism Ibuprofen Impairment Iodides Ions Knock-out Laboratories Length Life Light Link Liquid substance Literature Lung diseases Macromolecular Complexes Mammalian Cell Measurement Measures Mediating Metabolic Metabolism Methods Modeling Molecular Organism Pathway interactions Physiologic pulse Physiological Physiological Processes Population Process Production Proteins Proteolysis Regulation Reporting Research Role Scaffolding Protein Signal Transduction Societies Surface Synapses System Tertiary Protein Structure Testing Thyroglobulin Thyroid Diseases Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyronines Thyrotropin-Releasing Hormone Thyroxine Transport Process Tumor Suppression Ursidae Family Volatile Fatty Acids Work Xenopus oocyte apical membrane base body system cystic fibrosis patients density design fatty acid transport fetal follicular epithelial cell functional outcomes heart metabolism mutant novel novel therapeutic intervention outcome forecast overexpression prohormone protein protein interaction public health relevance scaffold solute thyronine trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): Thyroid hormones function in diverse and important physiological roles throughout the life an organism, ranging from the development of multiple organ systems to the regulation of metabolic rate. The thyroid is a unique collection of epithelial follicles that are organized to secrete the scaffold for hormone production, thyroglobulin, as well as iodinate and store the resultant thyroid hormone precursor. They also respond to the signaled need for thyroid hormone by processing and releasing thyroid hormones. Processes relevant to proper hormone synthesis take place within the follicle and also are compromised in many disease states. Our long-term goal is to understand how the thyroid follicular lumen composition is maintained. Our group recently positively established the presence of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in thyroid, where it can mediate thyroid anion secretion via an apically localized, cAMP-stimulated, conductive pathway for anion exit. Considering the importance of thyroid hormone to so many essential physiological processes, it is critical to identify and understand the role of CFTR in thyroid function. The present proposal aims to understand and develop a model describing the regulatory interaction between CFTR and SLC5A8, a solute transporter that is highly expressed at the apical membrane of the thyroid follicular epithelial cell. Our studies indicate that SLC5A8 activity depends on activation of CFTR, thus suggesting functional interactions. Among the reported functions for SLC5A8 are roles in iodide transport, short-chain fatty acid transport and tumor suppression. All are of potentially high relevance to thyroid health and disease and yet surprisingly little is known about them. CFTR regulation of other solute transport molecules of a different gene family (SLC26) is well-studied. Current models for CFTR regulation of SLC26s indicate protein-protein interactions that are facilitated by scaffolding molecules. SLC5A8 contains a well-studied protein interaction motif that is also found in CFTR, yet no information about its functional role exists in the literature. We hypothesize that CFTR regulates SLC5A8 via protein-protein interactions. Preliminary data using heterologous co-expression of CFTR and SLC5A8 in amphibian and mammalian cell model systems align with the predictions of the hypothesis. The proposed research strategy combines well-established methods to define both the molecular requirements for CFTR and SLC5A8 interaction(s) within macromolecular complex (es), as well as their regulatory crosstalk, i.e. the functional outcomes of interaction. Our proposed studies utilize complementary biochemical/cell biological approaches and functional electrophysiological and fluorimetric measurements. The resulting information will be integrated into models that can be iteratively challenged, developed and refined. The present proposal will be the first to test the hypothesis that both CFTR and SLC5A8 associate within a common macromolecular complex. Not only will all emergent findings be new and novel, but they potentially will impact the direction of multiple fields.

描述（由申请人提供）：甲状腺激素在生物体的整个生命过程中发挥多种重要的生理作用，从多器官系统的发育到代谢率的调节。甲状腺是一个独特的上皮细胞集合体，这些卵泡被组织起来分泌激素产生的支架，甲状腺球蛋白，以及碘化并储存合成的甲状腺激素前体。它们还通过处理和释放甲状腺激素来对甲状腺激素的信号需求做出反应。与适当的激素合成相关的过程发生在卵泡内，并且在许多疾病状态下也受到损害。我们的长期目标是了解甲状腺滤泡腔组成是如何维持的。我们的小组最近肯定了囊性纤维化跨膜传导调节因子（CFTR）在甲状腺中的存在，在那里它可以通过顶部定位的cAMP刺激的阴离子出口传导途径介导甲状腺阴离子分泌。考虑到甲状腺激素对许多基本生理过程的重要性，识别和理解CFTR在甲状腺功能中的作用至关重要。本提案的目的是了解和开发一个模型，描述CFTR和SLC 5A 8，一个溶质转运蛋白，是在甲状腺滤泡上皮细胞的顶端膜高度表达的调节之间的相互作用。我们的研究表明，SLC 5A 8的活性取决于CFTR的激活，从而表明功能相互作用。在报道的SLC 5A 8的功能中，有在碘化物转运、短链脂肪酸转运和肿瘤抑制中的作用。所有这些都与甲状腺健康和疾病具有潜在的高度相关性，但令人惊讶的是，人们对它们知之甚少。不同基因家族（SLC 26）的其他溶质转运分子的CFTR调节被充分研究。目前SLC 26的CFTR调控模型表明，支架分子促进了蛋白质-蛋白质相互作用。SLC 5A 8包含一个研究充分的蛋白质相互作用基序，也发现在CFTR中，但没有关于其功能作用的信息存在于文献中。我们假设CFTR通过蛋白质-蛋白质相互作用调节SLC 5A 8。在两栖动物和哺乳动物细胞模型系统中使用CFTR和SLC 5A 8的异源共表达的初步数据与假设的预测一致。提出的研究策略结合了成熟的方法来定义大分子复合物内CFTR和SLC 5A 8相互作用的分子要求，以及它们的调节串扰，即相互作用的功能结果。我们提出的研究利用互补的生物化学/细胞生物学方法和功能电生理和荧光测量。由此产生的信息将被整合到模型中，可以反复挑战，开发和完善。本提案将是第一个测试CFTR和SLC 5A 8在共同的大分子复合物内缔合的假设。不仅所有新发现都是新的和新颖的，而且它们可能会影响多个领域的方向。