Date of Award
Spring 5-2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmaceutical Sciences
First Advisor
Cintia E. Citterio, PhD
Second Advisor
Jennifer Totonchy, PhD
Third Advisor
Ajay Sharma, PhD
Abstract
Vertebrate life is unsustainable without thyroid hormones. The only known precursor for thyroid hormone synthesis is thyroglobulin (Tg), composed of upstream regions I-II-III and a C-terminal cholinesterase-like (ChEL) domain, which bears 47% similarity to acetylcholinesterase (AChE). Mutations in Tg cause congenital hypothyroidism, the most common congenital endocrinopathy affecting 1 in 2,000-4,000 newborns, with a varying degree of phenotypic manifestations. Tg protein, regulated by TSH, is secreted to the lumen of thyroid follicles, where thyroxine (T4) is formed primarily at the N-terminus, and triiodothyronine (T3) is formed primarily in the ChEL domain. Previous in vitro studies indicated that the isolated ChEL domain (following a signal peptide) is competent for dimerization, secretion, iodination, and T3 generation, but little to no T4 generation. However, the in vivo biological relevance of the Tg-ChEL domain (in the absence of the remaining Tg molecule) is entirely unknown. Furthermore, the functional effects of several Tg-ChEL mutations responsible for congenital hypothyroidism remain to be elucidated. This project has two main objectives. Objective 1 examines the thyroid histological characteristics of a genetically engineered mouse model built for selective expression of the Tg-ChEL domain. Objective 2 establishes an in vitro system using recombinant AChE as a reporter to enable future functional testing of ChEL domain mutations linked to congenital hypothyroidism. A deeper understanding of the functional role of the Tg’s ChEL domain could shed light on the spectrum of congenital hypothyroidism phenotypes, allowing for genotype-phenotype correlations for the future improvement of the disease diagnosis and treatment.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Morales-Rodriguez, B. Functional Characterization of the C-terminal Cholinesterase-Like (ChEL) Domain of the Thyroid Hormone Precursor Protein. [master’s thesis]. Irvine, CA: Chapman University; 2025. https://doi.org/10.36837/chapman.000664
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Endocrine System Diseases Commons, Other Pharmacy and Pharmaceutical Sciences Commons