Identifying the molecular determinants of pterygium progression

翼状胬肉是结膜的一种凸起的楔形纤维血管生长，迁移到透明的透明结膜中。 角膜。翼状胬肉会引起明显的不适，并可能通过诱导视力下降 不规则散光和视轴阻塞。导致翼状胬肉的确切分子机制 形成和进展未知。因此，目前尚无可用的药物疗法 翼状胬肉的预防或治疗。翼状胬肉和紫外线 (UV) 中炎症生物标志物上调 暴露是翼状胬肉形成的最重要的危险因素。然而，紫外线的作用机制 暴露会导致炎症，以及炎症反应是否在翼状胬肉中起致病作用 进展情况未知。我们的初步数据基于对人类翼状胬肉样本和正常人的分析 结膜显示人类翼状胬肉中非典型 NF-κB 信号激活的证据 与内源性逆转录病毒（ERV）的去抑制相结合。 ERV 是病毒逆转录因子，具有 整合到人类基因组中，它们的转录去抑制与增加 通过产生双链 RNA (dsRNA) 和 DNA (dsDNA) 产生细胞炎症，从而导致 dsRNA 和 dsDNA 传感器、RIG-I/MDA5/MAVS 和 cGAS-STING 先天免疫的激活 路径，分别。细胞固有的先天免疫途径的异常和失调激活已 通过激活非典型 NF-κB 信号传导参与细胞迁移和增殖。在 在这个提议中，我们将测试一个中心假设，即长期暴露于 UVB 会导致转录去 结膜细胞中 ERV 的抑制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。这个假设将 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 翼状胬肉来源细胞对非典型 NF-κB 信号传导的表型，这与 介导癌症模型中的迁移和侵袭表型。我们将建立翼状胬肉来源的细胞 从我们的临床实践中获得的手术标本。在目标 2 下，我们将确定是否存在慢性 UVB 暴露会导致非典型 NF-κB 信号传导上调，并测试非典型 NF-κB 信号传导是否被激活 NF-κB 信号传导是通过 ERV 的去抑制和下游 cGAS-STING 激活来介导的。通过利用 cGAS-STING 和非经典 NF-κB 关键成分的遗传和药理学操作 信号通路，我们寻求建立 UVB 暴露和迁移之间的机制联系 表型。该提案的总体目标是阐明潜在的分子机制 翼状胬肉的形成和进展，并确定适合药理学的分子靶标 干预。首席研究员是耶鲁大学的助理教授，并经营着一家独立的研究机构 实验室。我们的团队拥有完成拟议实验的临床专业知识和资源。

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.