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.
","abstract_html":"<p>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 (T<sub>4</sub>) is formed primarily at the N-terminus, and triiodothyronine (T<sub>3</sub>) is formed primarily in the ChEL domain. Previous <em>in vitro</em> studies indicated that the isolated ChEL domain (following a signal peptide) is competent for dimerization, secretion, iodination, and T<sub>3</sub> generation, but little to no T<sub>4</sub> generation. However, the <em>in vivo</em> 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 <em>in vitro</em> 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.</p>","abstract_has_math":false,"creators":["Morales-Rodriguez, Berenice"],"institution":null,"degree_name":"Master of Science (MS)","degree_level":"Thesis","degree_discipline":"Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["Cintia E. Citterio, PhD","Jennifer Totonchy, PhD","Ajay Sharma, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-01T07:00:00Z","date_published":"2025-05-01T07:00:00Z","updated_at":"2026-07-24T01:38:43Z","subjects":["thyroid","ChEL domain","thyroglobulin","congenital hypothyroidism","triiodothyronine","acetylcholinesterase","Congenital, Hereditary, and Neonatal Diseases and Abnormalities","Endocrine System Diseases","Other Pharmacy and Pharmaceutical Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/38","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Cintia E. Citterio, PhD","Jennifer Totonchy, PhD","Ajay Sharma, PhD"]},{"key":"dc:creator","label":"Author","values":["Morales-Rodriguez, Berenice"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science (MS)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["thyroid","ChEL domain","thyroglobulin","congenital hypothyroidism","triiodothyronine","acetylcholinesterase","Congenital, Hereditary, and Neonatal Diseases and Abnormalities","Endocrine System Diseases","Other Pharmacy and Pharmaceutical Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/38"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:source","label":"Dc Source","values":["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"]},{"key":"dc:title","label":"Title","values":["Functional Characterization of the C-terminal Cholinesterase-Like (ChEL) Domain of the Thyroid Hormone Precursor Protein"]}]}],"canonical_facts":{"dc:contributor":["Cintia E. Citterio, PhD","Jennifer Totonchy, PhD","Ajay Sharma, PhD"],"dc:creator":["Morales-Rodriguez, Berenice"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/38"],"dc:source":["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"],"dc:subject":["thyroid","ChEL domain","thyroglobulin","congenital hypothyroidism","triiodothyronine","acetylcholinesterase","Congenital, Hereditary, and Neonatal Diseases and Abnormalities","Endocrine System Diseases","Other Pharmacy and Pharmaceutical Sciences"],"dc:title":["Functional Characterization of the C-terminal Cholinesterase-Like (ChEL) Domain of the Thyroid Hormone Precursor Protein"],"thesis:degree_discipline":["Pharmaceutical Sciences"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Master of Science (MS)"]},"updated_at":"2026-07-24T01:38:43Z"}