Identifying the molecular determinants of pterygium progression

确定翼状胬肉进展的分子决定因素

基本信息

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
项目类别：
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

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

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项目摘要

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g是楔形的楔形纤维血管生长，可迁移到透明角膜。翼阵会引起严重的不适，并通过诱导而导致视力下降视觉轴的不规则散光和反对。导致翼状的精确分子机制形成和进展未知。因此，没有可用的医疗疗法可用于预防翼肉或治疗。炎症生物标志物在pterygium中被上调，紫外线（UV）暴露是翼状形成的最重要的危险因素。但是，紫外线的机制暴露会导致炎症，以及炎症反应是否在pterygium中起因作用进展未知。我们的初步数据基于对人翼肉样品和正常的分析结膜证明了人pterygia中非规范性NF-κB信号传导激活的证据再加上内源性逆转录病毒（ERV）的抑制。 ERV是病毒的追溯元素整合到人类基因组中，其转录消除抑制与增加有关通过产生双链RNA（DSRNA）和DNA（DSDNA）的细胞炎症，导致 DSRNA和DSDNA传感器的激活，RIG-I/MDA5/MAV和CGAS刺激先天免疫途径分别。细胞中性，先天免疫途径的异常和失调激活具有通过激活非典型的NF-κB信号传导，将其植入细胞迁移和增殖中。在该提案，我们将检验以下中心假设，即慢性UVB暴露会引起转录的影响。在结膜细胞中抑制ERV，导致细胞增殖和迁移增加 CGA-sting途径和下游非典型NF-κB信号的激活。这个假设将会使用两个独立目标进行测试。在AIM 1下，我们将测试迁移的认识依赖性翼状衍生细胞在非典型NF-κB信号传导上的表型，已与介导癌症模型中的迁移和侵入性表型。我们将建立翼状衍生的细胞在我们的临床实践中从手术标本中获得。在AIM 2下，我们将确定是否慢性UVB 暴露导致非典型NF-κB信号的上调，并测试非典型的激活 NF-κB信号传导是通过ERV的去抑制和下游CGAS刺激激活介导的。通过使用 CGA和非典型NF-κB的关键组成部分的遗传和药理操作信号通路，我们试图在UVB暴露与迁移之间建立机械联系表型。该提案的总体目标是阐明基础机制翼型形成和进展，并鉴定出适合药理的分子靶标干涉。首席调查员是耶鲁大学的助理教授，并拥有独立实验室。我们的团队拥有临床专业知识和资源来完成拟议的实验。