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）：该赠款专注于内质网（ER）蛋白质折叠和ER应力诱导的内分泌细胞死亡，使用甲状腺作为模型。这种疾病会影响每个器官系统。甲状腺是一种理想选择的模型系统，可以在其中研究这个问题，因为与胰腺β细胞的情况不同（在这种情况下，胰岛素的生产受损会导致对β细胞存活的恶性循环，这是由于甲状腺激素的产生量的限制，因此甲状腺激素的生产量不断扩展。通常，甲状腺合成甲状腺激素，这对于控制代谢，发育和脑功能至关重要。有限数量的有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％用于该蛋白质。甲状腺细胞等细胞具有“增压”蛋白质分泌途径，具有补品“生理ER应激”。至少有50个TG突变导致常染色体隐性先天性甲状腺功能减退症 - 所有这些产生蛋白质被夹住在ER内。许多TG突变与甲状腺肿有关，但对于其他TG突变，甲状腺的补偿性扩张被阻断。我们假设对于后者的TG突变体，蛋白毒性甲状腺细胞死亡限制了补偿性组织的扩张。在此应用程序中，我们提供了支持这一假设的新机械数据，并强调甲状腺是可用的最佳体内体内系统，用于研究ER应力介导的内分泌细胞衰竭。在甲状腺系统中，量化细胞死亡是直接的，重要的是，在活动物中，可以轻松地实时无创地遵循补偿性组织扩张的损失。我们未来5年的具体目的是：1。定义TG蛋白对其运输和蛋白质毒性的区域依赖性作用； 2。探索体内疗法，以促进ER超负荷的细胞存活（来自错误折叠的TG）； 3。要利用TGN - / - 小鼠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前体蛋白进行T4合成。

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）

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。

DOI：
10.1152/ajpcell.1993.265.3.c704
发表时间：
1993
期刊：
The American journal of physiology
影响因子：
0
作者：
Kim,PS;Kim,KR;Arvan,P
通讯作者：
Arvan,P

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

Thyroglobulin is selected as luminal protein cargo for apical transport via detergent-resistant membranes in epithelial cells.

甲状腺球蛋白被选为管腔蛋白货物，通过上皮细胞中的耐去污剂膜进行顶端运输。