Molecular regulation of fibroblast activation in Thyroid Eye Disease

甲状腺眼病(TED)，又称甲状腺相关眼眶病或眼病 常见的眼眶病理学。TED是一种自身免疫性疾病，发生在多达一半的Graves病患者中 疾病。在TED中，眼睛周围的组织会发炎，最终会重塑，导致隆起 眼睛周围肿胀，眼睑位置改变，复视。在最高级的案例中， 扩张的组织压迫视神经，导致视力受损。TED的这些临床表现 反映自身抗体引发的组织变化，这些自身抗体激活眼眶成纤维细胞，刺激细胞增殖 富含脂肪的脂肪细胞和形成瘢痕的肌成纤维细胞。眼眶成纤维细胞也会产生过量的 由透明质酸和胶原蛋白组成的细胞外基质，进一步增加了血管的大小和硬度 眼眶组织。目前，TED尚无治愈方法；皮质类固醇、放射治疗和手术是常规治疗方法。 用于管理TED症状和体征。胰岛素样生长因子1受体(IGF1R)Teproumumab 封闭抗体已经成为治疗TED的第一种疾病特异性治疗方法。然而，一个批判性的知识 限制我们对TED理解的一个缺口是，自身抗体如何激活眼眶成纤维细胞中的IGF1R信号 推广眼科疾病。IGF1R可刺激细胞增殖，增加肌成纤维细胞的形成。占优势的 TED中的抗原是促甲状腺激素受体(TSHR)。IGF1R如何与TSHR和TED相互作用 该病中的自身抗体是一个根本性且尚未解决的问题。一种可能的机制是通过 芳香烃受体(AHR)。AHR是一种配体激活的转录因子，它结合合成的和 天然衍生的芳香烃。AHR控制细胞生长、发育和免疫的各个方面 系统。有证据表明，AHR在体内和体外都能阻断TSHR和IGF1R信号转导。然而， 机制(S)还不清楚，AHR是否在TED中调节这些通路也是未知的。其中最 患TED的重要风险因素是吸烟。吸烟会激活一种称为缺氧的转录因子 诱导因子1α(HIF1a)。AHR和HIF1a竞争控制细胞的命运。吸烟可能会扰乱HIF1a- AHR平衡从而进一步增加IGF1R/TSHR信号转导。中心假设：AHR块 IGF1R/TSHR信号转导通路的缺失是TED病理生理过程中的主要事件。目标 1.明确AHR阻断眼眶成纤维细胞活化的分子途径(S)。目标2：确定 香烟烟雾暴露在抑制眼眶AHR的同时促进HIF1a和IGF1R信号转导的作用 成纤维细胞。目的3：评价AHR配体阻断TED自身抗体驱动的TSHR/IGF1R的能力 发信号。影响：我们的发现将显示AHR在TED中阻断TSHR和IGF1R信号。完成 这些特定的目的将建立一个分子机制，吸烟加剧IGF1R/TSHR信号在 泰德。此外，这些实验应该提供关键证据，证明激活AHR途径是一种新的和 治疗TED的可行治疗靶点。

Thyroid eye disease (TED), also referred to as thyroid-associated orbitopathy or ophthalmopathy is the most common orbital pathology. TED is an autoimmune disease that occurs in up to half of patients with Graves’ disease. In TED, the tissues surrounding the eye become inflamed and ultimately remodel to cause protrusion of the eyes, swelling around the eyes, alteration of lid position, and double vision. In the most advanced cases, the expanded tissues compress the optic nerve, causing vision impairment. These clinical manifestations of TED reflect tissue changes triggered by autoantibodies that activate orbital fibroblasts that stimulate proliferation of lipid-laden adipocytes and scar-forming myofibroblasts. Orbital fibroblasts also produce excessive amounts of extracellular matrix composed of hyaluronan and collagen, which further increases the size and stiffness of orbital tissue. There is presently no cure for TED; corticosteroids, radiation therapy, and surgery are routinely used to manage TED symptoms and signs. Teprotumumab, an insulin-like growth factor 1 receptor (IGF1R) blocking antibody has emerged as the first disease-specific treatment for TED. However, a critical knowledge gap that limits our understanding of TED is how autoantibodies activate IGF1R signaling in orbital fibroblasts to promote eye disease. IGF1R can stimulate proliferation and increase myofibroblast formation. The predominant antigen in TED is the thyroid stimulating hormone receptor (TSHR). How IGF1R interacts with TSHR and TED autoantibodies in the disease is a fundamental and unresolved question. One potential mechanism is through the aryl hydrocarbon receptor (AHR). The AHR is a ligand-activated transcription factor that binds synthetic and naturally derived aromatic hydrocarbons. The AHR controls aspects of cell growth, development and the immune system. Evidence suggests that AHR blocks TSHR and IGF1R signaling in vivo and in vitro. However, the mechanism(s) are unclear and whether the AHR regulates these pathways in TED is unknown. One of the most significant risk factors for developing TED is smoking. Smoking activates a transcription factor called hypoxia inducible factor 1 alpha (HIF1a). AHR and HIF1a compete to control cell fate. Smoking may disrupt the HIF1a- AHR balance thereby further increasing IGF1R/TSHR signaling. Central Hypotheses: The AHR blocks IGF1R/TSHR signaling, and loss of this interaction is a primary event in the pathophysiology of TED. Aim 1: Define the molecular pathway(s) by which the AHR blocks orbital fibroblast activation. Aim 2: Determine the role of cigarette smoke exposure in promoting HIF1a and IGF1R signaling while blocking AHR in orbital fibroblasts. Aim 3: Evaluate the ability of the AHR ligands to block TED autoantibody driven TSHR/IGF1R signaling. Impact: Our findings will show that AHR blocks TSHR and IGF1R signaling in TED. Accomplishing the specific aims will establish a molecular mechanism whereby smoking exacerbates IGF1R/TSHR signaling in TED. Further, the experiments should provide critical evidence that activating the AHR pathway is a novel and viable therapeutic target for treating TED.