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: 8712469
• 负责人: Sandra M McLachlan
• 金额: $ 33.9万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712469
• 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

描述（由申请人提供）：格雷夫斯甲状腺功能亢进症是由促甲状腺素受体（TSHR）的促甲状腺自身抗体（TSAb）引起的。有些小鼠品系对 TSHR 腺病毒免疫诱导的甲状腺功能亢进症敏感，有些则具有抗性。这种差异允许分析小鼠对甲状腺功能亢进症的遗传易感性。重组近交 (RI) 小鼠是由两个品系的后代重复兄妹交配而衍生的稳定品系。我们对基因型 CXB 和 BXH RI 菌株的研究表明，诱导的 TSHR 抗体和甲状腺功能亢进受不同染色体位点的影响。我们将基于这些发现如下： 1.甲状腺基线参数和对刺激的反应性的遗传控制：为了深入了解这些参数的遗传易感性，我们将通过以下方法研究源自血清 T4 和 Tg 值不同的亲本品系的 RI 小鼠： 测定 BXH 和 BXD RI 组小鼠中基线时和 TSH 刺激后的 T4 和 Tg 水平。进行连锁分析，以确定导致 T4、Tg 和 TSH 变异的染色体和基因座。 2. TSHR 抗体作为对 TSHR 免疫力的衡量标准。源自 TSHR 抗体反应不同的亲本品系的 AXB/BXA 和 DXB RI 小鼠（两个 RI 组分别为 A 与 B6 和 DBA/2 与 B6）将用 TSHR 腺病毒免疫，以： 确定诱导的 TSHR 抗体水平，以 TSH 结合抑制、TSAb 和 ELISA 测量。 将使用表达人和小鼠 TSHR 的 CHO 细胞来比较 TSAb 生物活性。 通过连锁分析识别与这些性状相关的染色体/基因座。 3.对促甲状腺抗体（TSAb）诱发的甲亢易感性。我们将进行以下研究： 用 TSHR 腺病毒免疫 AXB/BXA 和 BXD 组 RI 小鼠。为了克服 BXD 小鼠对诱导性甲状腺功能亢进症的抵抗力，我们将在 TSHR 腺病毒免疫之前耗尽 Treg。 确定影响 AXB/BXA 和 BXD 菌株中 iantibody 诱导的甲状腺功能亢进症的染色体/基因座。 总体而言，这些小鼠研究将为未来精炼遗传位点的研究奠定基础，并深入了解人类基因组宽阵列分析中格雷夫斯患者表型分层的方法