权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ANIMAL MODELS OF HYPERTHYROIDISM

甲亢动物模型

基本信息

批准号：
8884196
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884196
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 Cholecalciferol Confounding Factors (Epidemiology)Dendritic Cells Development Disabled Persons Disease Disease model Ensure Environmental Risk Factor Epitopes Generations Genes Goals Histology Human Hyperthyroidism Immunotherapy Inbred BALB C Mice Inbred NOD Mice Insulin-Dependent Diabetes Mellitus Intervention Investigation Iodide Peroxidase Lead Ligands Link Maintenance Measures Modeling Mouse Strains Mus NR4A1 gene Parents Pathogenesis 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 handicapping condition human disease immunological intervention in vivo insight intravenous injection mouse model novel 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.