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: 8824512
• 负责人: PETER ARVAN
• 金额: $ 49.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824512
• 关键词: Affect; Animals; Antelopes; Back; Beta Cell; Biological Models; Brain; Cattle; Cell Culture Techniques; Cell Death; Cell Respiration; Cell Survival; Cell surface; Cells; Cholinesterases; Cretinism; Data; Defect; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Endocrine; Endoplasmic Reticulum; Equation; Exhibits; Failure; Genes; Goat; Goiter; Grant; Growth; Health; Heterozygote; Human; Hypothyroidism; Inherited; Insulin; Knockout Mice; Knowledge; Life; Link; Malignant neoplasm of thyroid; Mediating; Medical; Metabolism; Modeling; Molecular; Mus; Mutation; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Pituitary Dwarfism; Predisposition; Prevention; Production; Protein Biosynthesis; Protein Precursors; Protein Secretion; Proteins; Rattus; Rodent; Scientist; Secondary to; Severity of illness; Sheep; Structure of beta Cell of islet; System; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Thyroxine; Time; Tissue Expansion; Transgenes; Vertebrates; base; biological adaptation to stress; body system; endoplasmic reticulum stress; genetic linkage analysis; growth hormone deficiency; in vivo; insight; interest; mutant; novel; novel strategies; protein misfolding; protein transport; selective expression

DESCRIPTION (provided by applicant): This grant concentrates on endoplasmic reticulum (ER) protein misfolding and ER stress-induced endocrine cell death, using the thyroid gland as a model. Diseases of this kind affect every organ system. The thyroid is an ideally-suited model system in which to study this problem because, unlike the situation in pancreatic beta cells (in which compromised insulin production leads to a vicious cycle of detrimental effects on beta cell survival caused by glucoliptoxicity), when thyroid hormone production is compromised, the hypothyroidism itself does not itself limit compensatory thyroid gland expansion. Normally, the thyroid gland synthesizes thyroid hormone, which is essential for control of metabolism, development, and brain function. A limited number of selectively-expressed thyroid gene products are involved in thyroid hormone production, including thyroglobulin (Tg). The thyroid can devote up to 50% of total protein synthesis to this one protein. Cells such as thyrocytes have a "supercharged" protein secretion pathway with tonic "physiological ER stress". At least 50 Tg mutations are responsible for autosomal recessive congenital hypothyroidism - all of these produce proteins entrapped within the ER. Many Tg mutations are associated with goiter, but for others, compensatory expansion of the thyroid gland is blocked. We hypothesize that for the latter group of Tg mutants, proteotoxic thyroid cell death limits compensatory tissue expansion. In this application, we provide new mechanistic data supporting this hypothesis, highlighting the thyroid gland as the best in vivo system available in which to study ER stress-mediated endocrine cell failure. Quantifying cell death is straightforward in the thyroid system, and importantly, the loss of compensatory tissue expansion can be easily followed in real time, noninvasively, in living animals. Our Specific Aims for the next 5 years are: 1. To define region-dependent effects of the Tg protein on its transport and proteotoxicity; 2. To explore in vivo therapies that facilitate cell survival in the face of ER overload (from misfolded Tg); and 3. To exploit Tgn-/- mice to examine classical ER stress response in thyroid cell death, and to uncover a previously unidentified precursor protein for T4 synthesis.

描述（由申请人提供）：该资助以甲状腺为模型，重点研究内质网 (ER) 蛋白错误折叠和 ER 应激诱导的内分泌细胞死亡。此类疾病影响每个器官系统。甲状腺是研究这个问题的理想模型系统，因为与胰腺β细胞的情况不同（其中胰岛素生成受损导致糖脂毒性导致对β细胞存活产生有害影响的恶性循环），当甲状腺激素生成受损时，甲状腺功能减退本身并不限制甲状腺的代偿性扩张。正常情况下，甲状腺合成甲状腺激素，这对于控制新陈代谢、发育和大脑功能至关重要。有限数量的选择性表达的甲状腺基因产物参与甲状腺激素的产生，包括甲状腺球蛋白（Tg）。甲状腺最多可将总蛋白质合成的 50% 用于这种蛋白质。甲状腺细胞等细胞具有“超负荷”的蛋白质分泌途径，具有强健的“生理内质网应激”。 至少 50 个 Tg 突变导致常染色体隐性遗传先天性甲状腺功能减退症 - 所有这些突变都会产生内质网内捕获的蛋白质。许多 Tg 突变与甲状腺肿有关，但对于其他突变，甲状腺的代偿性扩张受到阻碍。我们假设对于后一组 Tg 突变体，蛋白毒性甲状腺细胞死亡限制了代偿性组织扩张。在本申请中，我们提供了支持这一假设的新机制数据，强调甲状腺是研究内质网应激介导的内分泌细胞衰竭的最佳体内系统。量化甲状腺系统中的细胞死亡非常简单，重要的是，可以在活体动物中轻松、无创地实时跟踪补偿性组织扩张的丧失。我们未来 5 年的具体目标是： 1. 确定 Tg 蛋白对其转运和蛋白毒性的区域依赖性影响； 2. 探索在 ER 超载（来自错误折叠的 Tg）的情况下促进细胞存活的体内疗法； 3. 利用 Tgn-/- 小鼠来检查甲状腺细胞死亡中的经典 ER 应激反应，并发现以前未识别的 T4 合成前体蛋白。