Thyrocyte protein transport to the cell surface

描述（由申请人提供）：本资助以甲状腺为模型，重点研究内质网（ER）蛋白错误折叠和内质网应激诱导的内分泌细胞死亡。这种疾病影响到每一个器官系统。甲状腺是研究这一问题的理想模型系统，因为与胰腺β细胞的情况不同（胰岛素分泌受损导致糖脂毒性对β细胞生存的有害影响的恶性循环），当甲状腺激素分泌受损时，甲状腺功能减退本身并不限制代偿性甲状腺扩张。正常情况下，甲状腺合成甲状腺激素，这对控制新陈代谢、发育和脑功能至关重要。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）。甲状腺可以将总蛋白质合成的50%用于这种蛋白质。像甲状腺细胞这样的细胞有一个“增压”的蛋白质分泌途径，具有滋补性的“生理性内质网应激”。至少50个Tg突变与常染色体隐性先天性甲状腺功能减退症有关——所有这些突变都会产生被内质网包围的蛋白质。许多Tg突变与甲状腺肿有关，但对其他人来说，甲状腺的代偿性扩张被阻断。我们推测，对于后一组Tg突变体，蛋白质毒性甲状腺细胞死亡限制了代偿组织的扩张。在这项应用中，我们提供了新的机制数据来支持这一假设，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。在甲状腺系统中，定量细胞死亡是很简单的，重要的是，在活体动物中，可以很容易地实时、无创地跟踪代偿组织扩张的损失。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质毒性的区域依赖性作用；2. 探索在ER过载（由错误折叠的Tg）情况下促进细胞存活的体内疗法；和3。利用Tgn-/-小鼠研究甲状腺细胞死亡中的经典内质网应激反应，并发现一种以前未发现的T4合成前体蛋白。

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.