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.

Public Health Relevance

This grant concentrates on endoplasmic reticulum (ER) protein misfolding and ER stress-induced cell death, using the thyroid gland as a model. Diseases of this kind affect every organ system but the thyroid gland is an ideally-suited model system in which to study this problem. For example, 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 (diabetes) itself - when thyroid hormone production is compromised, the hypothyroidism does not harm thyrocytes. Indeed, ordinarily, hypothyroidism promotes compensatory thyroid gland expansion. However, we have developed a system that has the potential to provide deep mechanistic insight into what links ER protein misfolding to cell death, and we can quantify this in a straightforward way. Further, using the thyroid, an inability of compensatory tissue expansion is easily followed in real time, noninvasively, in living animals. The thyroid gland synthesizes thyroid hormone, which is essential for control of metabolism, development, and brain function. Thus, this application has broad general medical relevance. First, we highlight the thyroid gland as the best in vivo system available in which to study ER stress-mediated endocrine cell failure. Second, the grant provides a novel approach to understanding of thyroid hormone synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK040344-26A1
Application #
8693395
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Haft, Carol R
Project Start
1988-09-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
26
Fiscal Year
2014
Total Cost
$490,503
Indirect Cost
$175,067
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Di Jeso, Bruno; Arvan, Peter (2016) Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. Endocr Rev 37:2-36
Holzer, Guillaume; Morishita, Yoshiaki; Fini, Jean-Baptiste et al. (2016) Thyroglobulin Represents a Novel Molecular Architecture of Vertebrates. J Biol Chem 291:16553-66
Di Jeso, Bruno; Morishita, Yoshiaki; Treglia, Antonella S et al. (2014) Transient covalent interactions of newly synthesized thyroglobulin with oxidoreductases of the endoplasmic reticulum. J Biol Chem 289:11488-96
Wright, Jordan; Wang, Xiaofan; Haataja, Leena et al. (2013) Dominant protein interactions that influence the pathogenesis of conformational diseases. J Clin Invest 123:3124-34
Gualeni, Benedetta; Rajpar, M Helen; Kellogg, Aaron et al. (2013) A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Dis Model Mech 6:1414-25
Ferris, Sean P; Jaber, Nikita S; Molinari, Maurizio et al. (2013) UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum. Mol Biol Cell 24:2597-608
Lee, Jaemin; Di Jeso, Bruno; Arvan, Peter (2011) Maturation of thyroglobulin protein region I. J Biol Chem 286:33045-52
Lee, Jaemin; Arvan, Peter (2011) Repeat motif-containing regions within thyroglobulin. J Biol Chem 286:26327-33
Peteiro-Gonzalez, D; Lee, J; Rodriguez-Fontan, J et al. (2010) New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter. J Clin Endocrinol Metab 95:3522-6
Wang, Xiaofan; Lee, Jaemin; Di Jeso, Bruno et al. (2010) Cis and trans actions of the cholinesterase-like domain within the thyroglobulin dimer. J Biol Chem 285:17564-73

Showing the most recent 10 out of 15 publications