REGULATION OF MEMBRANE TRANSPORT BY THYROID HORMONE

甲状腺激素对膜运输的调节

• 批准号: 3242497
• 负责人: RICHARD S HABER
• 金额: $ 17.19万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242497
• 关键词: SDS polyacrylamide gel electrophoresis; autoradiography; gene expression; genetic regulation; genetic transcription; glucose transport; heart ventricle; hormone regulation /control mechanism; insulin sensitivity /resistance; laboratory rabbit; laboratory rat; liver; messenger RNA; northern blottings; nuclear runoff assay; nucleic acid hybridization; protein biosynthesis; striated muscles; tissue /cell culture; transport proteins; triiodothyronine; western blottings

Thyroid hormone stimulates cellular glucose uptake, an effect which is likely to play a key role in the enhancement of metabolic rate by the hormone. In the studies proposed herein the regulation of the glucose transporter gene by thyroid hormone will be examined in a cell culture system (ARL 15, a T3-responsive cell line derived from rat liver), and the in-vivo effects of thyroid hormone on tissue-specific forms of the glucose transporter will be determined. The effects of thyroid hormone on the rate of glucose transporter gene transcription and mRNA stability will be determined in ARL 15 cells, using a cDNA probe for the rat brain type of glucose transporter, whose mRNA is expressed in these cells and is increased by T3. In particular, the hypothesis that T3 may directly regulate glucose transporter gene transcription will be examined. In in-vivo studies in the rat, the effects of thyroid hormone on the expression of three recently described tissue-specific forms of the glucose transporter will be determined in skeletal muscle, heart, and liver. We will directly test the hypothesis that up-regulation of the muscle-type ("insulin-regulatable") glucose transporter gene expression by thyroid hormone is an important determinant of insulin sensitivity. In addition, the mechanism by which T3 regulates the abundance of this protein will be examined at the levels of gene transcription and messenger RNA stability, and the potential regulation of the liver-type transporter will be examined. By linking the stimulation of cellular glucose uptake by thyroid hormone to increased glucose transporter gene transcription, these studies may provide evidence that T3 regulates a gene whose expression is closely related to the enhancement of metabolic rate by thyroid hormone, confirming the importance of the transcriptional pathway of thyroid hormone action, and establishing the basis for future work on the regulation of glucose transporter gene expression. Moreover, the above studies have direct relevance to aspects of human disease, since regulation of the glucose transporter gene may play a role in the pathophysiology of diabetes mellitus, and may serve as a pace-setter for fuel utilization and metabolic rate in specific tissues in starvation and chronic illness.

甲状腺激素刺激细胞葡萄糖摄取， 可能在代谢率的提高中发挥关键作用， 激素. 在本文提出的研究中， 将在细胞培养物中检查甲状腺激素转运蛋白基因 系统（ARL 15，一种来自大鼠肝脏的T3应答细胞系）， 甲状腺激素对葡萄糖组织特异性形式的体内作用 运输商将确定。 甲状腺激素对葡萄糖转运蛋白基因表达的影响 将在ARL 15细胞中测定转录和mRNA稳定性，使用 大鼠脑型葡萄糖转运蛋白的cDNA探针，其mRNA为 在这些细胞中表达，并通过T3增加。 特别是 T3可能直接调节葡萄糖转运蛋白基因假说 转录将被检查。 在大鼠的体内研究中，甲状腺激素对 三种最近描述的葡萄糖的组织特异性形式的表达 将在骨骼肌、心脏和肝脏中测定转运蛋白。 我们 将直接检验这一假设，即肌肉型的上调 （“胰岛素可调节”）葡萄糖转运蛋白基因表达的甲状腺 激素是胰岛素敏感性重要决定因素。 此外，本发明还提供了一种方法， T3调节这种蛋白质丰度的机制将是 在基因转录和信使RNA稳定性的水平上进行检查， 肝脏型转运蛋白的潜在调节将是 考察 通过将甲状腺激素刺激细胞葡萄糖摄取与 增加葡萄糖转运蛋白基因转录，这些研究可能提供 证据表明，T3调节一个基因，其表达与 甲状腺激素代谢率的提高，证实了 甲状腺激素作用的转录途径的重要性，以及 为今后的葡萄糖调节工作奠定基础 转运蛋白基因表达 此外，上述研究具有直接意义 与人类疾病相关，因为葡萄糖的调节 转运蛋白基因可能在糖尿病的病理生理中起作用 并可作为燃料利用和代谢的领跑者 饥饿和慢性疾病中特定组织的死亡率。