GENETIC SUSCEPTIBILITY TO GRAVES'-LIKE HYPERTHYROIDISM IN MICE

小鼠对格雷夫斯样甲状腺功能亢进症的遗传易感性

• 批准号: 8502473
• 负责人: Sandra M McLachlan
• 金额: $ 32.71万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502473
• 关键词: Adenoviruses; Affect; Animal Model; Antibodies; Antibody Formation; Autoantibodies; Binding; Brothers; Chinese Hamster Ovary Cell; Chromosomes; Chromosomes, Human, Pair 17; Data; Data Linkages; Databases; Development; Disease; Enzyme-Linked Immunosorbent Assay; Future; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Health; Human; Human Genome; Hyperthyroidism; Immune Response Genes; Immunity; Immunization; Immunoglobulins; Inbred Mouse; Inbreeding; Light; Link; Measures; Modeling; Mouse Strains; Mus; Nature; Parents; Patients; Play; Predisposition; Recombinant Inbred Strain; Recombinants; Regulatory T-Lymphocyte; Resistance; Role; Serum; Sister; Stratification; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroid stimulating immunoglobulins; Thyrotropin Receptor; Thyroxine; Variant; Woman; base; genetic linkage analysis; genome wide association study; genome-wide; insight; trait

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.

描述（由申请人提供）：Graves的甲状腺功能亢进是由甲状腺刺激自身抗体（TSAB）引起的，甲状腺激素受体（TSHR）。一些小鼠菌株易感性，有些是耐药性的，对TSHR-腺病毒免疫引起的甲状腺功能亢进。这种差异允许分析小鼠对甲状腺功能亢进的遗传敏感性。重组近交（RI）小鼠是由两种菌株后代的兄弟X姐妹垫子得出的稳定线。我们在基因分型CXB和BXH RI菌株中的研究表明，诱导的TSHR抗体和甲状腺功能亢进受不同的染色体基因座的影响。我们将基于这些发现如下： 1。遗传控制甲状腺素的参数和对刺激的反应性：为了洞悉这些参数的遗传易感性，我们将研究来自血清T4和TG值不同的RI小鼠，通过：确定在基线和BXH和BXD RI集中的TSH刺激下的T4和TG刺激下的T4和TG水平。进行连锁分析以识别染色体和基因座，负责T4，TG和TSH的变异性。 2。TSHR抗体作为对TSHR免疫的度量。 AXB/BXA和DXB RI小鼠，来自TSHR抗体反应不同（分别为两种RI集的A对B6和B6和DBA/2与B6的伴侣），将用TSHR-辅助病毒免疫到：确定诱导的TSHR抗体在TSHR抗体水平上测量的TSHR抗体水平，因为TSHR抗体水平是THSH Inibition Inibition IniSAb和Elisa，TSHR抗体水平。 使用表达人和小鼠TSHR的CHO细胞比较TSAB生物活性。 通过链接分析识别与这些特征相关的染色体/基因座。 3。甲状腺刺激抗体（TSAB）诱导的甲状腺功能亢进症的敏感性。我们将进行以下研究：用TSHR-腺病毒免疫AXB/BXA和BXD套件。为了克服对BXD小鼠诱导的甲状腺功能亢进症的耐药性，我们将在TSHR-腺病毒免疫之前耗尽Treg。 确定影响IANTIBODY诱导的AXB/BXA和BXD菌株中甲状腺功能亢进症的染色体/基因座。 总体而言，这些在小鼠中的研究将为未来的研究提供完善遗传基因座的基础，并深入了解人类基因组广泛阵列分析中坟墓患者表型分层的方法 公共卫生相关性：坟墓的甲状腺功能亢进是由甲状腺受体刺激抗体（TSHR）引起的，该抗体模仿TSH刺激。该疾病是多基因术，但大型患者组的基因组广泛扫描未能揭示除MHC以外的常见基因。我们将在遗传型的近交小鼠中使用诱发的Graves的甲状腺功能亢进模型，以建立开发TSHR抗体和升高血清甲状腺素的遗传基础，目的是为未来的人类基因组广泛的阵列分析提供深入了解坟墓患者的洞察力。