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Thyrocyte protein transport to the cell surface

甲状腺细胞蛋白质转运至细胞表面

基本信息

批准号：
9462701
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
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9462701
关键词：
Affect Animals Antelopes Back Beta Cell Biological Models Brain Carrier Proteins Cattle Cell Culture Techniques Cell Death Cell Respiration Cell Survival Cell surface Cells Cholinesterases Cretinism Data Defect Detection Development Diabetes Mellitus Diagnosis Disease Dwarfism Endocrine Endoplasmic Reticulum Equation Exhibits Failure Genes Goat Goiter Grant Growth Heterozygote Human Hypothyroidism Inherited Insulin Knockout Mice Knowledge 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 Conformation 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 biological adaptation to stress body system endoplasmic reticulum stress gene product genetic linkage analysis growth hormone deficiency in vivo insight interest mutant novel novel strategies protein misfolding protein transport proteotoxicity public health relevance selective expression

项目摘要

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）：该基金集中在内质网（ER）蛋白质错误折叠和ER应激诱导的内分泌细胞死亡，使用甲状腺作为模型。这类疾病会影响每一个器官系统。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（胰岛素产生受损导致糖脂毒性对β细胞存活产生有害影响的恶性循环），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甲状腺代偿性扩张。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。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%用于这一蛋白质。细胞如甲状腺细胞具有“增压”蛋白质分泌途径，具有滋补性“生理性ER应激”。至少有50个Tg突变导致常染色体隐性遗传性先天性甲状腺功能减退症-所有这些都产生了ER内的蛋白质。许多Tg突变与甲状腺肿有关，但对于其他人来说，甲状腺的代偿性扩张受阻。我们推测，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。在这个应用程序中，我们提供了新的机制数据支持这一假设，突出甲状腺作为最好的体内系统，研究ER应激介导的内分泌细胞衰竭。量化甲状腺系统中的细胞死亡是直接的，重要的是，在活体动物中，可以很容易地在真实的时间、非侵入性地跟踪补偿性组织扩张的损失。我们未来五年的具体目标是：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疗法;和3.利用Tgn-/-小鼠研究甲状腺细胞死亡中经典的ER应激反应，并发现一个以前未鉴定的T4合成前体蛋白。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.

DOI：
10.1210/jc.2009-2109
发表时间：
2010-06
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
D. Peteiro-González;Jaemin Lee;J. Rodriguez-Fontan;Isabel Castro-Piedras;J. Cameselle-Teijeiro;Andrés Beiras;Susana B. Bravo;Clara V. Alvarez;D. Hardy;H. Targovnik;Peter Arvan;J. Lado-Abeal
通讯作者：
D. Peteiro-González;Jaemin Lee;J. Rodriguez-Fontan;Isabel Castro-Piedras;J. Cameselle-Teijeiro;Andrés Beiras;Susana B. Bravo;Clara V. Alvarez;D. Hardy;H. Targovnik;Peter Arvan;J. Lado-Abeal

Disulfide-linked aggregation of thyroglobulin normally occurs during nascent protein folding.

甲状腺球蛋白的二硫键连接聚集通常发生在新生蛋白质折叠过程中。