The overall goal of this project is to advance understanding of certain fundamental, molecular processes involved in the regulation of thyroid cellular function. Specifically, it is proposed to perform the following studies: 1. Studies on genes other than thyroglobulin that are regulated by TSH. a. Initial studies on TSH-induced genes already cloned from FRTL5 cells. i) nucleotide sequencing (in part). ii) determination of whether the increased levels of mRNA reflect increased transcription. iii) time-course of stimulation of cellular mRNA levels by TSH. b. In selected genes of interest it is planned to: i) sequence the entire structural (cDNA) gene; ii) characterize the gene in the FRTL5 genome; iii) localize and study the promoter area; iv) study the function of the gene product by enhancing or inhibiting the expression of the gene in thyroid cells. 2. Studies on the human thyroid peroxidase (TPO) gene. a. Identification and sequencing of the full-length human TPO cDNA gene. b. Characterization of the TPO gene in the human genome. c. Determination of TPO mRNA levels in normal and pathological human thyroid tissue. d. Study on the potential genetic basis for abnormal TPO activity in selected diseased thyroid glands. e. Study of the regulation of TPO mRNA expression in thyroid cells. 3. Studies on ras and myc proto-oncogene expression in the thyroid. a. Studies on the mechanism by which TSH activates ras gene expression. b. Examination of the role of the ras and myc proto-oncogenes (alone or together) on selected thyroid cellular differentiated functions. i) transfection of FRTL5 cells with plasmids containing the c-ras and c-myc genes. ii) transfection of FRTL5 cells with """"""""antisense"""""""" mRNA plasmid constructs designed to specifically inhibit the functions of these genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK019289-15
Application #
3226330
Study Section
Endocrinology Study Section (END)
Project Start
1976-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
15
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
McLachlan, Sandra M; Lesage, Sylvie; Collin, Roxanne et al. (2017) Genes Outside the Major Histocompatibility Complex Locus Are Linked to the Development of Thyroid Autoantibodies and Thyroiditis in NOD.H2h4 Mice. Endocrinology 158:702-713
Ludwig, Ralf J; Vanhoorelbeke, Karen; Leypoldt, Frank et al. (2017) Mechanisms of Autoantibody-Induced Pathology. Front Immunol 8:603
McLachlan, Sandra M; Aliesky, Holly; Banuelos, Bianca et al. (2017) Variable Effects of Dietary Selenium in Mice That Spontaneously Develop a Spectrum of Thyroid Autoantibodies. Endocrinology 158:3754-3764
Rapoport, Basil; Banuelos, Bianca; Aliesky, Holly A et al. (2016) Critical Differences between Induced and Spontaneous Mouse Models of Graves' Disease with Implications for Antigen-Specific Immunotherapy in Humans. J Immunol 197:4560-4568
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 37:114-34
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 2016:23-42
Chen, Chun-Rong; Salazar, Larry M; McLachlan, Sandra M et al. (2015) Deleting the Redundant TSH Receptor C-Peptide Region Permits Generation of the Conformationally Intact Extracellular Domain by Insect Cells. Endocrinology 156:2732-8
Rapoport, Basil; Aliesky, Holly A; Chen, Chun-Rong et al. (2015) Evidence that TSH Receptor A-Subunit Multimers, Not Monomers, Drive Antibody Affinity Maturation in Graves' Disease. J Clin Endocrinol Metab 100:E871-5
Chen, Chun-Rong; Hubbard, Paul A; Salazar, Larry M et al. (2015) Crystal structure of a TSH receptor monoclonal antibody: insight into Graves' disease pathogenesis. Mol Endocrinol 29:99-107
Rapoport, Basil; Aliesky, Holly A; Banuelos, Bianca et al. (2015) A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. J Immunol 194:4154-61

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