Identifying the molecular determinants of pterygium progression

确定翼状胬肉进展的分子决定因素

• 批准号: 10656905
• 负责人: Mathieu Fahim Bakhoum
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656905
• 关键词: Astigmatism; Biological Markers; Cancer Model; Cell Proliferation; Cells; Chronic; Clinical; Conjunctival Pterygium; Cornea; Coupled; DNA; Data; Dependence; Double-Stranded RNA; Endogenous Retroviruses; Genetic; Genetic Transcription; Goals; Growth; Human; Human Genome; Inflammation; Inflammatory Response; Intervention; Laboratories; Link; Mediating; Medical; Molecular; Molecular Target; Obstruction; Operative Surgical Procedures; Pathway interactions; Phenotype; Play; Prevention; Principal Investigator; Production; Resources; Retroelements; Risk Factors; Role; Running; Sampling; Shapes; Signal Pathway; Signal Transduction; Specimen; Stimulator of Interferon Genes; Testing; UV Radiation Exposure; Ultraviolet B Radiation; Universities; Up-Regulation; Viral; Vision; Visual; cell motility; clinical practice; conjunctiva; derepression; experimental study; innate immune pathways; migration; pharmacologic; professor; sensor

Pterygium is a raised wedge-shaped fibrovascular growth of the conjunctiva that migrates into the transparent cornea. Pterygium causes significant discomfort and can lead to a decline in vision through induction of irregular astigmatism and obstruction of visual axis. The exact molecular mechanism leading to pterygium formation and progression is unknown. Consequently, there are no available medical therapies available for pterygium prevention or treatment. Inflammation biomarkers are upregulated in pterygium, and ultraviolet (UV) exposure is the most significant risk factor for pterygium formation. However, the mechanism by which UV exposure leads to inflammation, and whether an inflammatory response plays a causative role in pterygium progression is unknown. Our preliminary data based on analysis of human pterygium samples and normal conjunctiva demonstrate evidence of activation of non-canonical NF-κB signaling in human pterygia that is coupled with de-repression of endogenous retroviruses (ERVs). ERVs are viral retroelements that have integrated into the human genome, and their transcriptional de-repression has been associated with increased cellular inflammation through the production of double-stranded RNA (dsRNA) and DNA (dsDNA), leading to the activation of the dsRNA and dsDNA sensors, RIG-I/MDA5/MAVS and the cGAS-STING innate immune pathways, respectively. Aberrant and dysregulated activation of cell-intrinsic, innate immune pathways has been implicated in cellular migration and proliferation through activation of non-canonical NF-κB signaling. In this proposal, we will test the central hypothesis that chronic UVB exposure induces transcriptional de- repression of ERVs in conjunctival cells leading to increased cellular proliferation and migration through activation of the cGAS–STING pathway and downstream non-canonical NF-κB signaling. This hypothesis will be tested using two independent aims. Under Aim 1, we will test the epistatic dependency of the migratory phenotype of pterygium-derived cells on non-canonical NF-κB signaling, which has been implicated in mediating a migratory and invasive phenotype in cancer models. We will establish pterygium-derived cells obtained from surgical specimens at our clinical practice. Under Aim 2, we will determine whether chronic UVB exposure leads to upregulation of non-canonical NF-κB signaling, and test whether activation of non-canonical NF-κB signaling is mediated by de-repression of ERVs and downstream cGAS-STING activation. By utilizing genetic and pharmacologic manipulation of key components of the cGAS-STING and non-canonical NF-κB signaling pathways, we seek to establish a mechanistic link between UVB exposure and a migratory phenotype. The overarching goal of this proposal is to elucidate the molecular mechanisms underlying pterygium formation and progression, and identify molecular targets that are amenable to pharmacologic intervention. The Principal Investigator is an Assistant Professor at Yale University and runs an independent laboratory. Our team has the clinical expertise and the resources to complete the proposed experiments.

翼状胬肉是结膜的一种隆起的楔形纤维血管生长， 角膜翼状胬肉引起明显的不适，并可通过诱导 不规则散光和视轴阻塞。翼状胬肉发病的确切分子机制 形成和发展是未知的。因此，没有可用的药物治疗可用于 翼状胬肉的预防或治疗。炎症生物标志物在翼状胬肉中上调，紫外线（UV） 暴露是翼状胬肉形成的最重要的危险因素。然而，紫外线的机制 暴露导致炎症，以及炎症反应是否在翼状胬肉中起致病作用 进展不明。我们的初步数据基于对人类翼状胬肉样本和正常翼状胬肉样本的分析。 结膜显示在人翼状胬肉中非典型NF-κB信号传导激活的证据， 再加上内源性逆转录病毒（ERV）的去阻遏。ERV是病毒逆转录因子， 整合到人类基因组中，并且它们的转录去抑制与增加 通过产生双链RNA（dsRNA）和DNA（dsDNA）引起细胞炎症， dsRNA和dsDNA传感器、RIG-I/MDA 5/MAVS和cGAS-STING先天免疫的激活 路，分别。细胞内在的先天免疫途径的异常和失调激活， 通过激活非经典NF-κB信号传导参与细胞迁移和增殖。在 这个建议，我们将测试中心假设，慢性UVB暴露诱导转录去， 抑制结膜细胞中的ERV，导致细胞增殖和迁移增加， cGAS-STING通路和下游非经典NF-κB信号传导的激活。这一假设将 使用两个独立的目标进行测试。在目标1下，我们将测试迁移的上位依赖性， 表型的pk10衍生的细胞对非经典NF-κB信号，这已经牵连到 在癌症模型中介导迁移和侵袭表型。我们将建立一个从肺中提取的细胞 在我们的临床实践中从手术标本中获得。在目标2下，我们将确定慢性UVB是否 暴露导致非经典NF-κB信号转导的上调，并测试非经典NF-κB信号转导的激活是否与非经典NF-κ B信号转导有关。 NF-κB信号传导由ERV的去抑制和下游cGAS-STING活化介导。通过利用 cGAS-STING和非经典NF-κB关键组分的遗传和药理学操作 信号通路，我们试图建立一个机制之间的联系UVB暴露和迁移 表型这项建议的首要目标是阐明潜在的分子机制， 翼状胬肉的形成和进展，并确定适合药理学治疗的分子靶点 干预首席研究员是耶鲁大学的助理教授， 实验室我们的团队拥有临床专业知识和资源来完成拟议的实验。