Thyroid follicular cells perform multiple functions that depend upon epithelial polarity, including the secretion of thyroglobulin (Tg) into the lumen of thyroid follicles, uptake of iodide and its use for covalent modification of Tg, and the manufacture and delivery of thyroid hormones to the bloodstream. Defects in several of these steps are well-recognized causes of hypothyroidism. This application focuses on dissecting these processes at the cellular level. A major area of concentration is the traffic of newly synthesized Tg from its site of synthesis in the endoplasmic reticulum (ER) to its delivery in the follicle lumen. New evidence suggests that initial folding of nascent Tg-is a complicated process involving a family of helper proteins known as molecular chaperones in the ER. A second area is the protein targeting mechanism that allows Tg to be directed to the follicle lumen instead of the bloodstream. Using cultured thyroid epithelial monolayers on porous filters, which allow experimental access to both apical and basolateral surfaces, the investigators have now identified (by purifying and partial sequencing) a second protein that --unlike Tg-is secreted with basolateral preference. Thus, thyrocytes exhibit true intracellular sorting in the distal secretory pathway. The investigator hypothesizes that sorting signals in regulated secretory proteins lead to apical-specific targeting in thyrocytes; specific transfection experiments are proposed to test this idea. A third area is the distribution and delivery of apical and basolateral plasma membrane proteins that are essential for hormonogenesis; a straightforward experimental plan is proposed to examine thyroid cell surface polarity. Finally, a recent breakthrough indicates that the filter-polarized thyrocytes both synthesize T4 and secrete it with a marked basolateral preference. The investigators hypothesize that the polarized secretion of thyroxine is mediated by specific transporters in the thyrocyte basolateral membrane.In the last Specific Aim the investigator proposes an initial characterization of this transport using a variety of pharmacologic agents that act as thyroid inhibitors and stimulators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040344-09
Application #
2016309
Study Section
Endocrinology Study Section (END)
Project Start
1988-09-01
Project End
1996-11-30
Budget Start
1996-09-25
Budget End
1996-11-30
Support Year
9
Fiscal Year
1996
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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Citterio, Cintia E; Veluswamy, Balaji; Morgan, Sarah J et al. (2017) De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. J Biol Chem 292:15434-15444
Qi, Ling; Tsai, Billy; Arvan, Peter (2017) New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation. Trends Cell Biol 27:430-440
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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
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
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
Lee, Jaemin; Di Jeso, Bruno; Arvan, Peter (2011) Maturation of thyroglobulin protein region I. J Biol Chem 286:33045-52

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