Thyrocyte protein transport to the cell surface

描述(申请人提供)：这项资助集中于内质网(ER)蛋白错误折叠和内质网应激诱导的内分泌细胞死亡，以甲状腺为模型。这类疾病影响到每个器官系统。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，当甲状腺激素产生受损时，甲状腺功能减退症本身并不限制代偿性甲状腺的扩张。正常情况下，甲状腺合成甲状腺激素，这是控制新陈代谢、发育和大脑功能所必需的。少数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)。甲状腺可以将高达总蛋白质合成的50%用于这一种蛋白质。甲状腺细胞等细胞在紧张性“生理性内质网应激”下具有“超负荷”的蛋白质分泌途径。至少有50个TG突变是常染色体隐性遗传性先天性甲状腺功能减退症的原因--所有这些突变都会产生困在内质网内的蛋白质。许多TG突变与甲状腺肿大有关，但对其他人来说，甲状腺的代偿性扩张被阻止了。我们假设，对于后一组TG突变，蛋白毒性甲状腺细胞死亡限制了代偿性组织的扩张。在这一应用中，我们提供了支持这一假说的新的机制数据，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。量化细胞死亡在甲状腺系统中是直截了当的，重要的是，在活体动物中，可以很容易地实时、非侵入性地追踪代偿组织扩张的丧失。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.探索在面对ER过载(来自错误折叠的TG)时促进细胞存活的体内治疗方法；3.利用TGN-/-小鼠来研究甲状腺细胞死亡中经典的ER应激反应，并揭示一种以前未知的T4合成的前体蛋白。

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.