Molecular regulation of fibroblast activation in Thyroid Eye Disease

甲状腺眼病成纤维细胞活化的分子调控

基本信息

批准号：
10475581
负责人：
Collynn Fremont Woeller
金额：
$ 37.35万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10475581
关键词：
Adipocytes Adrenal Cortex Hormones Antigens Aromatic Hydrocarbons Aryl Hydrocarbon Receptor Attenuated Autoantibodies Autoimmune Diseases Automobile Driving Binding Blindness Blocking Antibodies Cell Fate Control Cell Proliferation Cells Cicatrix Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Culture Techniques Data Diplopia Disease Equilibrium Event Extracellular Matrix Eye Eye diseases Fibroblasts Functional disorder Genes Genetic Transcription Goals Graves&apos Disease Growth Factor Growth Factor Receptors Growth Hormone Receptor Growth and Development function Hyaluronan IGF1 gene Immune system In Vitro Individual Inflammatory Insulin-Like-Growth Factor I Receptor Knowledge Ligands Lipids Mediating Mediator of activation protein Modeling Molecular Myofibroblast Ocular orbit Operative Surgical Procedures Optic Nerve Orbital Diseases Pain Pathologic Pathology Pathway interactions Patients Plasma Positioning Attribute Production Proliferating Proteomics Radiation therapy Receptor Signaling Regulation Risk Factors Role Signal Transduction Signs and Symptoms Small Interfering RNA Smoke Smoking Swelling Symptoms Technology Testing Therapeutic Thyroid Gland Thyrotropin Receptor Time Tissue Expansion Tissues Visual impairment Work aryl hydrocarbon receptor ligand cell growth cigarette smoke cytokine experimental study exposure to cigarette smoke hypoxia inducible factor 1 in vivo modifiable risk mutant novel receptor expression therapeutic target three dimensional cell culture thyroid associated ophthalmopathies transcription factor transcriptome sequencing

项目摘要

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.

甲状腺眼病（TED），也称为引用相关的轨道病或眼科病是最多的常见的轨道病理学是一种自身免疫性疾病，最多发生在坟墓中疾病。眼睛，眼睛周围肿胀，盖子位置的改变以及双视力。扩展的组织压缩了Opttic神经，导致视力障碍。反映由激活轨道刺激增殖的自身抗体触发的组织变化富含脂质的脂肪细胞和形成疤痕的肌纤维细胞。细胞外基质由透明质酸和胶原蛋白组成，这进一步增加了大小和刚度轨道组织。用于管理TED症状和体征。阻断抗体已成为TED的第一种特异性疾病治疗方法。限制我们对TED的理解的差距是自身抗体如何激活轨道纤维的IGF1R信号传导到促进眼睛疾病 TED中的抗原是刺激的激素受体（TSHR）。疾病中的自身抗体是一个基本且尚未解决的问题。芳基碳氢化合物受体（AHR）。天然衍生的芳烃。系统。机理是叔叔，AHR是否调节TED中的途径是未知的。开发TED的重要危险因素是吸烟。诱导因子1α（HIF1A）。 AHR平衡，从而进一步增加IGF1R/TSHR信号。 IGF1R/TSHR信号传导，这种相互作用的丧失是TED病理生理学的主要事件。 1：定义分子途径（S），AHR阻止轨道成纤维细胞激活2：确定您在阻断轨道中AHR时，香烟烟雾暴露在促进HIF1A和IGF1R信号中的作用成纤维细胞3：评估AHR配体以阻止TED自动抗体驱动的TSHR/IGF1R 信号：我们的发现将阻止TSHR和IGF1R信号具体目的将建立一种分子机制，吸烟加剧IGF1R/TSHR信号传导 TED。可行的治疗靶标。