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周期中发挥着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。甲状腺是上皮细胞的独特集合组织分泌用于激素生成、甲状腺球蛋白的支架的滤泡作为碘酸盐并储存由此产生的甲状腺激素前体。它们还通过处理和释放甲状腺激素来响应甲状腺激素的信号需求。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会受到损害。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地确定了甲状腺中存在囊性纤维化跨膜电导调节器（CFTR），它可以通过顶端局部的、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重要生理过程的重要性，识别和了解 CFTR 在甲状腺功能中的作用至关重要。本提案旨在理解和开发一个模型，描述 CFTR 和 SLC5A8 之间的调节相互作用，SLC5A8 是一种在甲状腺滤泡上皮细胞顶膜高度表达的溶质转运蛋白。我们的研究表明 SLC5A8 活性取决于 CFTR 的激活，因此表明功能相互作用。据报道，SLC5A8 的功能包括碘化物转运、短链脂肪酸转运和肿瘤抑制。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。 CFTR 对不同基因家族 (SLC26) 的其他溶质转运分子的调节已得到充分研究。当前 SLC26 的 CFTR 调节模型表明支架分子促进了蛋白质-蛋白质相互作用。 SLC5A8 包含一个经过充分研究的蛋白质相互作用基序，该基序也在 CFTR 中发现，但文献中没有关于其功能作用的信息。我们假设 CFTR 通过蛋白质-蛋白质相互作用调节 SLC5A8。在两栖动物和哺乳动物细胞模型系统中使用 CFTR 和 SLC5A8 异源共表达的初步数据与假设的预测一致。所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 SLC5A8 相互作用的分子要求，以及它们的调控串扰，即相互作用的功能结果。我们提出的研究利用互补的生化/细胞生物学方法以及功能性电生理学和荧光测量。由此产生的信息将被集成到可以迭代挑战、开发和完善的模型中。本提案将首次检验 CFTR 和 SLC5A8 在共同大分子复合物中结合的假设。所有的新发现不仅都是新颖的，而且可能会影响多个领域的方向。