ANIMAL MODELS OF HYPERTHYROIDISM

甲亢动物模型

• 批准号: 6819977
• 负责人: Sandra M McLachlan
• 金额: $ 35.96万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6819977
• 关键词: ANIMAL; MODELS; HYPERTHYROIDISM

EXCEEDTHE SPACEPROVIDED. 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 PERFORMANCE SITE ========================================Section End===========================================

EXCEEDTHE SPACEPROVIDED。Graves病是一种常见的人类自身免疫性疾病，由刺激TSH受体（TSHR）的自身抗体引起。目前还没有这种疾病的自发动物模型。我们将使用两种诱导小鼠模型；“裸”TSHR-DNA疫苗接种和“Shimojo”方法（注射表达tshr的成纤维细胞）。通过这些模型，我们将分析TSHR免疫反应中的以下问题：微生物或缺乏自身耐受性的影响：我们将研究TSHR- dna疫苗与微生物产物联合接种所诱导的TSHR抗体的滴度和功能活性，以及TSHR敲除小鼠对TSHR不能获得自身耐受性。2. 细胞因子和细胞相互作用：野生型小鼠和b细胞敲除小鼠将被用来确定(a)哪种细胞因子是由tshrr蛋白攻击的脾细胞产生的；(b) CD4+或CD8+ T细胞是否参与反应；3、TSHR特异性T细胞识别的表位：合成的TSHR肽将用于确定T细胞识别的表位(a)克隆自接种TSHR dna的BALB/c小鼠；(b) TSHR基因敲除小鼠对TSHR缺乏耐受性；(c)转基因HLA的小鼠易患（DR3）或预防（DQ6） Graves病。自然加工的TSHR肽也将被研究。共刺激信号：将探索共刺激分子的作用(a)在体外通过使用抗体阻断CD40/CD40-1配体和CD28/B7-1/2相互作用；(b)使用CD28、CD40、B7-1或B7-2基因被敲除的小鼠进行体内实验；(c)在小鼠体内注射抗B7-1（或对照）和TSHR -成纤维细胞（表达B7-1）。5. TSHR的剪切和脱落作用：A亚基在TSHR的非剪切或脱落中起重要作用；(b)研究抗原(如传真照片)甘露糖受体性能 ======================================== 节结束 ===========================================