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

• 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
• 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' 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

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），又称甲状腺相关性眼病或眼病最多