Identifying the molecular determinants of pterygium progression

翼状胬肉是一种隆起的楔形纤维血管生长的结膜，它迁移到透明的 眼角膜。翼状胬肉会引起严重的不适，并可通过诱导 散光不规则，视轴受阻。翼状胬肉发生的确切分子机制 其形成和发展尚不清楚。因此，没有可用的医疗疗法来治疗 翼状胬肉的预防或治疗。炎症生物标志物在翼状胬肉和紫外线(UV)中上调 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到致病作用 进展尚不清楚。我们的初步数据是基于对人翼状胬肉样本和正常人的分析 结膜显示非典型的NF-κB信号在人类翼状胬肉中被激活，即 再加上内源性逆转录病毒(ERV)的抑制作用。ERV是一种病毒逆转录元件，具有 整合到人类基因组中，它们的转录抑制与增加有关 通过产生双链RNA(DsRNA)和DNA(DsDNA)引起的细胞炎症，导致 DsRNA和dsDNA传感器、RIG-I/MDA5/MAVS的激活和cGAS刺痛的先天免疫 分别是路径。细胞内源性、先天免疫通路的异常和失调激活 通过激活非规范的NF-κB信号参与细胞的迁移和增殖。在……里面 在这项提议中，我们将检验中心假设，即长期暴露于UVB会导致转录水平下降。 抑制ERV在结膜细胞中的表达可促进细胞的增殖和迁移 CGAS-STING通路的激活和下游非规范的NF-κB信号转导。这一假说将 使用两个独立的目标进行测试。在目标1下，我们将检验迁移者的上位依赖 翼状胬肉来源细胞的表型对非典型的NF-κB信号的影响，这已被涉及到 在癌症模型中调节迁移和侵袭表型。我们将建立翼状胬肉来源的细胞 从我们临床诊所的手术标本中获得。在目标2下，我们将确定慢性紫外线是否 暴露导致非典范的NF-κB信号上调，并检测非典范的激活 NF-κB信号转导是通过下调ERV和下游cGAS-STING的激活来实现的。通过利用 CGAS-刺激性和非典型性核因子-κB关键成分的遗传和药理学调控 信号通路，我们试图在UVB暴露和迁徙之间建立一种机械联系 表型。这个提议的首要目标是阐明潜在的分子机制。 翼状胬肉的形成和发展，并确定符合药物作用的分子靶点 干预。首席调查员是耶鲁大学助理教授，经营着一项独立的 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。

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.