GENETIC SUSCEPTIBILITY TO GRAVES'-LIKE HYPERTHYROIDISM IN MICE

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DESCRIPTION (provided by applicant): Graves' hyperthyroidism is caused by thyroid stimulating autoantibodies (TSAb) to the thyrotropin receptor (TSHR). Some mouse strains are susceptible, and some are resistant, to developing hyperthyroidism induced by TSHR- adenovirus immunization. This difference permits analyzing the genetic susceptibility to hyperthyroidism in mice. Recombinant inbred (RI) mice are stable lines derived by repeated brother x sister matings of the progeny of two strains. Our studies in genotyped CXB and BXH RI strains revealed that induced TSHR antibodies and hyperthyroidism are influenced by different chromosomal loci. We will build on these findings as follows: 1. Genetic controlofthyroidbaseline parameters and responsiveness to stimulation : To obtain insight into the genetic susceptibility for these parameters, we will study RI mice derived from parental strains differing in serum T4 and Tg values by: Determining T4 and Tg levels at baseline and after TSH stimulation in BXH and BXD RI sets of mice. Performing linkage analysis to identify chromosomes and loci responsible for variability in T4, Tg and TSH. 2. TSHR antibodies as a measure of immunity to the TSHR . AXB/BXA and DXB RI mice, derived fromparental strains differing in TSHR antibody responses (A versus B6 and DBA/2 versus B6 for the two RI sets, respectively) will be immunized with TSHR-adenovirus to: Determine induced TSHR antibody levels measured as TSH binding inhibition, TSAb and ELISA. TSAb bioactivity will be compared using CHO cells expressing human and mouse TSHR. Identify by linkage analysis the chromosomes/loci associated with these traits. 3. Susceptibility to hyperthyroidism induced by thyroid stimulating antibodies (TSAb). We will perform the following studies: Immunize AXB/BXA and BXD sets of RI mice with TSHR-adenovirus. To overcome resistance to induced hyperthyroidism in BXD mice, we will deplete Treg before TSHR-adenovirus immunization. Determine chromosomes/loci influencing iantibody induced hyperthyroidism in AXB/BXA and BXD strains. Overall, these studies in mice will provide the basis for future studies refining genetic loci and provide insight into approaches for phenotypic stratification of Graves' patients in human genome wide array analyses PUBLIC HEALTH RELEVANCE: Graves' hyperthyroidism is caused by thyroid stimulating antibodies to the thyrotropin receptor (TSHR) that mimic stimulation by TSH. The disease is multigenic but genome wide scans in large patient groups fail to reveal common genes except for MHC. We will use an induced model of Graves' hyperthyroidism in genetically typed inbred mice to establish the genetic basis for the development of TSHR antibodies and elevated serum thyroxine with the goal of providing insight into subsetting Graves' patients for future human genome wide array analyses.