The Role of Master Epigenetic Regulators in Ocular Chemical Injury

主表观遗传调节因子在眼部化学损伤中的作用

• 批准号: 10687249
• 负责人: Massoud Motamedi
• 金额: $ 48万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687249
• 关键词: Acetylation; Acute; Anatomy; Angiography; Antibodies; BRD2 gene; Binding; Bioinformatics; Biological Models; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Chemical Injury; Chemical Weapons; Chronic; Clinical Research; Clinical Trials; Complex; Cornea; Corneal Injury; Corneal Opacity; Data; Defect; Development; Disease; Disease Management; ETS1 gene; Edema; Effectiveness; Endothelial Cells; Epigenetic Process; Epithelium; Eye Injuries; Fibrosis; Gene Expression; Genes; Genetic Transcription; Genomics; Histone Acetylation; Histones; Human; Imaging Techniques; Immune response; Immunohistochemistry; Individual; Inflammation; Inflammatory; Injury; Intervention; Lysine; Mechlorethamine; Mediating; Modeling; Molecular; Monitor; Mus; Mustard; Mustard Gas; N-terminal; Nucleosome Core Particle; Optical Coherence Tomography; Oryctolagus cuniculus; Pathway interactions; Patients; Persons; Phase; Phosphorylation; Physiological; Play; Positive Transcriptional Elongation Factor B; Process; Production; Protein Family; RNA Polymerase II; Reaction; Reader; Reagent; Recovery; Reporting; Role; Safety; Scaffolding Protein; Severities; Skin injury; Tail; Terrorism; Testing; Testis; Topical application; Transcript; Transcription Coactivator; Transforming Growth Factor beta; Vascular Endothelial Growth Factors; Vesicants; Visual impairment; Work; analog; angiogenesis; burn therapy; corneal burn; corneal epithelium; cost; effective therapy; efficacy evaluation; in vivo; inhibitor; injured airway; insight; limbal; mouse model; neovascularization; novel; ocular imaging; pharmacologic; recruit; response; severe injury; success; transcription factor; transcriptome sequencing; translational potential

The Role of Master Epigenetic Regulators in Ocular Chemical Injury SUMMARY Mustard vesicants including sulfur mustard (SM) and nitrogen mustard (NM) cause severe respiratory, skin, and ocular injuries. They have been used as a chemical weapon in the warfare and also impose a potential threat to civilians as they could be used by the terrorists' attack. Ocular injuries in particular corneal injury were prevalent in SM-exposed victims. Inflammation, neovascularization and fibrosis are three major problems and players in mustard-induced corneal injury, yet the underlying mechanisms are largely unknown, which limits the development of effective managements for the disease. The BET (bromodomain and extra-terminal domain) family proteins, including universally expressed BRD2, BRD3 and BRD4 and testis-specific BRDt, are epigenetic readers. They recognize and bind to acetylated lysine (KAc) within the N-terminal tail protruding from the histone core of the nucleosome, and act as scaffold proteins to recruit transcription factors and the positive transcription elongation factor b (P-TEFb) complex, which phosphorylates and releases paused RNA polymerase II (RNAPII) to transcript the transcription factor-targeted genes. The BETs play a key role in inflammation, neovascularization and fibrosis in many disease but their role in ocular chemical injury is unknown. We now provide compelling evidence suggesting that BETs have a key role in corneal mustard injury and propose to further explore this novel mechanism. We will test the hypothesis that NM injury induces corneal inflammation, neovascularization and fibrosis via activation of master epigenetic regulator BETs using mouse and rabbit models, selective BTE inhibitors, state of the art in vivo ocular imaging techniques including optical coherence tomography (AS-OCT) and OCT-angiography (OCT-A), and genomic profiling and immunohistochemistry approaches. The proposed work will allow us to define the role of BETs in mustard- induced injury by characterizing the contributions of BD1 and BD2 in corneal injury, elucidating the underlying mechanisms, and testing whether BET inhibition could effectively treat acute and delayed injury. Considering the success that has been reported in developing BET blockers with acceptable safety profiles and promising efficacy in several phase I and II clinical trials, BET inhibitors may offer high translational potentials for being tested and eventually used in clinical studies.

主表观遗传调节剂在眼部化学损伤中的作用 概括 芥末囊泡物在内 和眼部受伤。它们在战争中被用作化学武器，也施加了潜力 对平民的威胁，因为恐怖分子的袭击可以使用。眼部受伤特别是角膜损伤 在暴露的受害者中普遍存在。炎症，新血管形成和纤维化是三个主要问题， 芥末引起的角膜损伤的玩家，但基本机制在很大程度上未知，这限制了 开发该疾病的有效管理。下注（溴结构域和末端 域）蛋白质，包括普遍表达的BRD2，BRD3和BRD4和睾丸特异性BRDT 表观遗传学读者。他们识别并结合N末端尾巴内的乙酰化赖氨酸（KAC） 从核小体的组蛋白核心，充当支架蛋白，以募集转录因子和 正转录伸长因子B（P-TEFB）复合物，磷酸化并释放暂停的RNA 聚合酶II（RNAPII），用于转录因子靶向基因。赌注在 许多疾病中的炎症，新血管形成和纤维化，但它们在眼部化学损伤中的作用是 未知。我们现在提供了令人信服的证据，表明赌注在角膜芥末损伤中起关键作用 并建议进一步探索这种新型机制。我们将测试NM损伤引起的假设 通过激活主要表观遗传调节剂，使用了角膜炎症，新血管形成和纤维化 小鼠和兔模型，选择性BTE抑制剂，体内眼部成像技术的最新技术包括 光学相干断层扫描（AS-OCT）和OCT-Angiography（OCT-A）以及基因组分析和 免疫组织化学方法。拟议的工作将使我们能够定义赌注在芥末中的作用 通过表征BD1和BD2在角膜损伤中的贡献，阐明基础，引起损伤 机制，并测试BET抑制是否可以有效治疗急性和延迟损伤。考虑 在开发具有可接受安全性和有前途的可接受的BET阻滞剂方面已经报道了成功的成功 在多个I期和II期临床试验中的功效，BET抑制剂可能会为其提供高的转化潜力 测试并最终用于临床研究。