甲状腺毒症是指由于机体中循环甲状腺激素水平过高，导致较强的甲状腺激素作用的一种临床状态。其多发于女性及老年人群，最典型的疾病类型是格雷夫斯病(Graves' disease, GD)。眼病是甲状腺毒症最常见的症状之一， 50％的Grave患者患有明显的眼病，其发病率占眼眶病变的首位，有90％的患者呈现典型的眼球突出特征。研究认为，甲状腺眼病与甲状腺毒症都是由TSHR刺激诱发的，迄今对其发病机制尚不完全清楚。本课题组在长期饲养的树鼩种群中，发现约有2%的动物自发产生了眼部病变，且多表现为眼突症状。这些发病动物中雌性比例约占80%，且多为中老年雌性，与人类Graves眼病患者流行病学特点相似。另外，这些发病动物多表现为生育力较差，精神萎靡，经检查存在不同程度的甲状腺病变。通过对发病树鼩临床特征观察，我们推测树鼩可能自发产生甲状腺毒症并发眼突。因此，本研究通过大体解剖、病理分析、血清学检测、转录组测序检测甲状腺毒症指标，从临床症状、生化指标、分子机制的角度分析并阐述树鼩自发甲状腺毒症的特征。并试图通过转录组结果分析来寻找致病通路，将这些结果与人类甲状腺毒症进行对比分析，为树鼩作为甲状腺毒症研究模型提供理论依据。

根据甲状腺毒症发病特点，本研究主要针对中老年雌性树鼩展开研究，通过与同性别、同年龄临床表现正常的动物进行比较分析，得到以下结果：

1. 通过大体解剖观察以及病理结果分析，发现所收集的眼突树鼩均伴随不同程度的甲状腺异常，甲状腺多表现为肿大、颜色变深；病理显示具有明显的滤泡上皮增生呈立方状，滤泡萎缩，胶质排空。眼部表现为不同程度的眼眶肌肉萎缩，眼肌淋巴细胞浸润及眼部脂肪病变，表明树鼩能够自发产生甲状腺病和眼病，且树鼩自发性甲状腺病与眼病具有关联性。

2. 血清学检测结果显示，病变组树鼩其血清中游离甲状腺素（Free thyroxine，FT4）和促甲状腺素受体抗体（Thyrotropin receptor antibody，TSHRAb）水平显著高于正常组，差异有统计学意义(P＜0.05)。甲状腺过氧化物酶抗体（Thyroid peroxidase antibody，TPOAb）、甲状腺球蛋白抗体（Thyroglobulin antibody，TGAb）、促甲状腺激素（thyrotropin，TSH）、IFN-γ水平与正常组对比差异无统计学意义(P＞0.05)，但有少数个体TPOAb、 TGAb、IFN-γ水平高于正常组。

3.通过两组甲状腺转录组测序发现差异基因显著富集于皮质醇合成分泌信号通路、补体和凝血级联反应信号通路、cAMP信号通路、MAPK信号通路、内吞信号通路、细胞粘附分子信号通路上，它们可能参与了甲状腺毒症的病理过程。

4. 通过RT-qPCR检测皮质醇合成分泌信号通路及补体和凝血级联反应信号通路中显著上调基因的表达情况，验证了这两条通路可能参与了树鼩甲状腺毒症病理过程。

Thyrotoxicosis is a clinical condition resulting from excess of circulating thyroid hormone in the body , which leads to a strong thyroid hormone effect. It mostly occurs in women and the elderly, and the most typical type of disease is Graves' disease (GD). Ophthalmopathy is one of the most common symptoms of thyrotoxicosis. 50% of Grave patients suffer from obvious ophthalmopathy, the incidence of which is the first in orbital disease, and 90% of patients present typical features of exophthalmos. Studies have shown that thyroid ophthalmopathy and thyrotoxicosis are both induced by TSHR stimulation, and their pathogenesis is not yet fully understood. In the population of long-term raised tree shrews, we found that about 2% of the animals spontaneously develop eye diseases, and most of them are eye protrusions. Females account for about 80% of the diseased animals, and most of them are middle-aged and elderly females, similar to the epidemiological characteristics of human Graves’ ophthalmopathy. In addition, most of these diseased animals showed poor fertility and weak, and they were found to have varying degrees of thyroid disease after examination. Based on the observation of the clinical characteristics of the diseased tree shrews, we speculate that the tree shrews may spontaneously develop thyrotoxicosis with eye protrusions. Therefore, gross anatomy, pathological analysis, serological testing, were used to detect thyrotoxicosis indicators, and transcriptome sequencing was analyzed the characteristics of tree shrew spontaneous thyrotoxicosis from the perspective of clinical symptoms, biochemical indicators, and molecular mechanisms. Trying to find pathogenic pathways by analyzing transcriptome results, comparing these results with characteristics of human thyrotoxicosis, and providing a theoretical basis for tree shrews as a animal model for thyrotoxicosis.

According to the characteristics of thyrotoxicosis, this study mainly focuses on middle-aged and elderly female tree shrews. A comparative analysis of animals of the same sex and the same age with normal clinical manifestations was carried out, and the following results were obtained:

1. According to gross anatomical observation and pathological analysis, it was found that these eye-protruding tree shrews were accompanied by varying degrees of thyroid abnormalities. The thyroid gland was mostly enlarged and darkened in color; pathology showed obvious follicular epithelial hyperplasia and cubic shape and follicular atrophy , Gum is drained. The eyes showed varying degrees of orbital muscle atrophy, ocular muscle lymphocyte infiltration and ocular fatty lesions, indicating that tree shrews can spontaneously produce thyroid disease and eye disease, and tree shrew spontaneous thyroid disease is associated with eye disease.

2. Serological test results showed that the serum levels of free thyroxine (FT4) and thyrotropin receptor antibody (TSHR Ab) in the tree shrews of the lesion group were significantly higher than those of the normal group, There is a significant difference (P <0.05). The Thyrotropin (TSH), Thyroid peroxidase antibody (TPO Ab), Thyroglobulin antibody (TG Ab), IFN-γ levels did not differ significantly between the two groups. (P> 0.05), but a few individuals have higher levels of TPO Ab, TG Ab, and IFN-γ than the normal group.

3. By the transcriptome sequencing of the thyroid, it was found that the differential genes were significantly enriched in the cortisol synthesis and secretion signal pathway, complement and coagulation cascade signal pathway, cAMP signal pathway, MAPK signal pathway, endocytosis pathway, cell adhesion molecules pathway , which may be involved in thyrotoxicosis Pathological process.

4. The expression of up-regulated genes detected by RT-PCR of the cortisol synthesis and secretion pathway and complement and coagulation cascades pathway. It verified that these two pathways may be involved in the pathological process of tree shrew thyrotoxicosis.