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ANIMAL MODELS OF HYPERTHYROIDISM

甲亢动物模型

基本信息

批准号：
9275466
负责人：
Sandra M McLachlan
金额：
$ 38.25万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275466
关键词：
Adjuvant Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Apoptosis Applications Grants Autoantibodies Autoantigens Autoimmune Diseases Back Benign Breeding CD40 Ligand Cells Chemicals Cholecalciferol Confounding Factors (Epidemiology)Dendritic Cells Development Disabled Persons Disease Disease model Ensure Environmental Risk Factor Epitopes Generations Genes Goals Graves&apos Disease Histology Human Hyperthyroidism Immunotherapy Inbred BALB C Mice Inbred NOD Mice Injectable Insulin-Dependent Diabetes Mellitus Intervention Investigation Iodide Peroxidase Lead Ligands Link Maintenance Measures Modeling Mouse Strains Mus NR4A1 gene Parents Pathogenesis Pathogenicity Pathologic Physiologic pulse Production Property Protein Subunits Protocols documentation Regulatory T-Lymphocyte Role Selenium Signal Transduction Splenocyte T-Lymphocyte T-Lymphocyte Epitopes TSH receptor antibody Testing Therapeutic Thyroglobulin Thyroid Function Tests Thyroid Gland Thyroid stimulating immunoglobulins Thyroiditis Thyrotropin Receptor Time Transgenes Transgenic Mice Transgenic Organisms Vaccination central tolerance common treatment congenic falls human disease immunological intervention in vivo insight intravenous injection mouse model novel novel therapeutics programs public health relevance receptor receptor expression vector

项目摘要

DESCRIPTION (provided by applicant): Graves' disease is an autoimmune disorder caused by pathogenic thyroid stimulating antibodies (TSAb) that mimic TSH in activating the TSH receptor (TSHR). The resulting hyperthyroidism can be treated but there is no cure. A critical barrier to studying its pathogenesis, as well as investigation of novel therapies, is that Graves' disease only occurs in humans. Therefore, the development of a mouse model that spontaneously develops pathogenic TSHR antibodies would represent a highly significant advance, providing insight into the pathogenesis of Graves' disease and facilitating investigation of potential approaches for specific immunotherapy for cure, rather than treatment of this common human disease. By crossing transgenic mice that express the human TSHR A-subunit in the thyroid to another mouse strain that spontaneously develops thyroiditis, we have developed the first animal model, hTSHR/NOD-H2h4 mice, that spontaneously develops pathogenic TSAb. Our first aim will be to optimize and characterize the hTSHR/NOD-H2h4 mouse model. We will complete back-crossing to the parent strain for a total of 10 generations to ensure that hTSHR/NOD-H2h4 mice have 100% of NOD-H2h4 background genes. We will then determine the time course of pathogenic TSHR antibody generation, titer and maintenance of levels, as well as characterize the model for thyroid function, thyroid histology and the full compendium of thyroid autoantibodies. Our second aim is to investigate factors that may influence the spontaneous development of pathogenic TSAb in this model including the role of central tolerance by measuring intrathymic expression of the human TSHR A-subunit (and the other thyroid antigens). We will also assess the influence of regulatory T cells on TSHR Ab development, determine epitopes recognized by T-cells, as well as the influence of environmental factors (vitamin D3 and selenium) on TSAb levels. Our third aim is to suppress the development and, particularly on-going production, of TSAb. Approaches to be used will be injecting TSHR A-subunit protein, an approach that may cause deviation of TSAb to a benign, non-pathogenic form. We will also attempt to induce tolerance to the TSHR by a number of approaches, including injecting immature dendritic cells pulsed with purified TSHR A-subunit protein, as well as by blocking the "second signal" between T-cells and antigen presenting cells.

描述（由申请人提供）：格雷夫斯病是一种由致病性甲状腺刺激抗体（TSAb）引起的自身免疫性疾病，该抗体在激活TSH受体（TSHR）时模拟TSH。由此产生的甲状腺功能亢进症可以治疗，但没有治愈。研究其发病机制以及研究新疗法的一个关键障碍是格雷夫斯病仅发生在人类中。因此，自发产生致病性TSHR抗体的小鼠模型的开发将代表高度显著的进步，提供对Graves病的发病机制的洞察，并促进对用于治愈的特异性免疫疗法的潜在方法的研究，而不是对这种常见人类疾病的治疗。通过将甲状腺中表达人TSHR A亚基的转基因小鼠与另一种自发发生甲状腺炎的小鼠品系杂交，我们开发了第一种自发发生致病性TSAb的动物模型hTSHR/NOD-H2 h4小鼠。我们的第一个目标是优化和表征hTSHR/NOD-H2 h4小鼠模型。我们将完成与亲本品系的回交共10代，以确保hTSHR/NOD-H2 h4小鼠具有100%的NOD-H2 h4背景基因。然后，我们将确定致病性TSHR抗体产生的时间过程，滴度和水平的维持，以及表征甲状腺功能，甲状腺组织学和甲状腺自身抗体的完整纲要的模型。我们的第二个目的是调查因素，可能会影响自发发展的致病性TSAb在这个模型中，包括通过测量胸腺内表达的人TSHR A-亚基（和其他甲状腺抗原）的中枢耐受性的作用。我们还将评估调节性T细胞对TSHR Ab发育的影响，确定T细胞识别的表位，以及环境因素（维生素D3和硒）对TSAb水平的影响。我们的第三个目标是抑制TSAb的发展，特别是正在进行的生产。将使用的方法是注射TSHR A亚基蛋白，这种方法可能导致TSAb偏离为良性、非致病性形式。我们还将尝试通过多种方法诱导对TSHR的耐受性，包括注射用纯化的TSHR A亚基蛋白脉冲的未成熟树突状细胞，以及通过阻断T细胞和抗原呈递细胞之间的“第二信号”。

项目成果

期刊论文数量（65）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thyrotropin receptor-DNA vaccination of transgenic mice expressing HLA-DR3 or HLA-DQ6b.

对表达 HLA-DR3 或 HLA-DQ6b 的转基因小鼠进行促甲状腺素受体 DNA 疫苗接种。

DOI：
10.1089/105072503322511300
发表时间：
2003
期刊：
Thyroid : official journal of the American Thyroid Association.
影响因子：
0
作者：
Pichurin,Pavel;Chen,Chun-Rong;Pichurina,Oxana;David,Chella;Rapoport,Basil;McLachlan,SandraM
通讯作者：
McLachlan,SandraM

Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice.

自我耐受和慢性刺激在野生型和转基因小鼠中腺病毒诱导的促甲状腺素受体抗体长期持续存在中的作用。