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ANIMAL MODELS OF HYPERTHYROIDISM

甲亢动物模型

基本信息

批准号：
7161480
负责人：
Sandra M McLachlan
金额：
$ 34.09万
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 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7161480
关键词：
AKR/N Mouse Adenovirus Vector Adenoviruses Alleles Animal Disease Models Animal Model Antibodies Antigen Receptors Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Diseases B-Lymphocytes CD28 gene CD80 gene CD8B1 gene Cleaved cell CpG dinucleotide DNA Data Dendritic Cells Development Epitopes Fibroblasts G-Protein-Coupled Receptors Goals Graves&apos Disease HLA-DQ6 HLA-DR3 Antigen Human Hyperthyroidism IDEC-114 Monoclonal Antibody Immune response Immunoglobulin G In Vitro Inbred BALB C Mice Inositol Interferons Interleukin-4 Interleukin-5 Knockout Mice Lipopolysaccharides MHC Class II Genes Membrane Proteins Modeling Mus Organism Peptides Play Process Proteins Role Self Tolerance Signal Transduction Splenocyte T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes TNF gene TNFRSF5 gene TSH receptor antibody Tail Testing Thyrotropin Receptor Transgenic Mice Vaccinated Vaccination Wild Type Mouse cell type cytokine in vivo knockout gene macrophage mannose receptor microbial mouse model novel strategies particle plasmid DNA receptor response synthetic peptide

项目摘要

Graves' disease is a common human autoimmune disorder caused by autoantibodies that stimulate the TSH receptor (TSHR). There are no spontaneous animal models of the disease. We will use two induced mouse models; "naked" TSHR-DNA vaccination, and the "Shimojo" approach (injecting TSHR-expressing fibroblasts). With these models, we will analyze the following issues in the immune response to the TSHR:- 1. Influence of micro-organisms or lack of self tolerance: We will study the titers and functional activity of TSHR antibodies induced by TSHR-DNA vaccination in combination with microbial products, as well as in TSHR-knockout mice that cannot acquire self tolerance to the TSHR. 2. CYtokine and cellular interactions: Wild type mice and B-cell knockout mice will be used to determine (a) which cytokines are produced by splenocytes challenged with TSHR-protein; (b) whether CD4+ or CD8+ T cells are involved in the response; (c) if B cells are required to induce memory T cells specific for the TSHR, 3, Epitopes recognized by TSHR-specific T cells: Synthetic TSHR peptides will be used to determine the epitopes recognized by T cells (a) cloned from TSHR-DNA vaccinated BALB/c mice; (b) TSHR knockout mice that lack tolerance to the TSHR; (c) mice transgenic for HLA that predispose (DR3) or protect against (DQ6) Graves' disease. Naturally 3rocessed TSHR peptides will also be studied, 3. Co-stimulatory signals: The role of co-stimutatory molecules will be explored (a) in vitro by using antibodies to block CD40/CD40-1igand and CD28/B7-1/2 interactions; (b) in vivo using mice with disrupted genes ("knockouts") for CD28, CD40, B7-1 or B7-2; (c) in vivo by injecting mice with anti-B7-1 (or control) together with TSHR -fibroblasts (that express B7-1). 5. Role of TSHR cleavage and shedding: We heavily glycosylated A subunit plays a role non-cleaving or shedding TSHR; (b) examining antigens (such as TPO) to the mannose receptor

格雷夫斯病是一种常见的人类自身免疫性疾病，由自身抗体刺激TSH受体引起