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: 10515906
• 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/10515906
• 关键词: Acute; Anatomy; Angiography; Antibodies; BRD2 gene; Binding; Bioinformatics; Biological Models; Bromodomain; Chemical Injury; Chemical Weapons; Chronic; Clinical Research; Complex; Cornea; Corneal Injury; Corneal Opacity; Data; Defect; Development; Disease; Disease Management; ETS1 gene; Edema; Effectiveness; Endothelial Cells; Epigenetic Process; Epithelial; 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; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; 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; base; burn therapy; corneal burn; corneal epithelium; cost; effective therapy; in vivo; inhibitor; injured airway; insight; limbal; mouse model; neovascularization; novel; ocular imaging; recruit; response; 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.

表观遗传调控因子在眼化学损伤中的作用 总结 芥子类起疱剂，包括硫芥子气（SM）和氮芥子气（NM），可引起严重的呼吸道、皮肤， 还有眼部受伤它们在战争中被用作化学武器， 这是对平民的威胁，因为他们可能被恐怖分子的袭击所利用。眼部损伤，特别是角膜损伤， 在SM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， 芥末诱导的角膜损伤的参与者，但其潜在的机制在很大程度上是未知的，这限制了 发展有效的疾病管理。BET（布罗莫结构域和额外末端） 结构域）家族蛋白，包括普遍表达的BRD 2、BRD 3和BRD 4以及睾丸特异性BRDt， 表观遗传学的读者它们识别并结合N-末端尾部突出的乙酰化赖氨酸（KAc） 从核小体的组蛋白核心，并作为支架蛋白招募转录因子， 正转录延伸因子B（P-TEF B）复合物，磷酸化并释放暂停的RNA 在一些实施方案中，RNA聚合酶II（RNAPII）用于转录转录因子靶向的基因。BET在以下方面发挥着关键作用 炎症、新血管形成和纤维化，但它们在眼化学损伤中作用 未知我们现在提供了令人信服的证据，表明BETs在角膜芥末损伤中起关键作用 并建议进一步探索这一新机制。我们将检验NM损伤诱导 通过激活主要表观遗传调节因子BET的角膜炎症、新血管形成和纤维化 小鼠和兔模型，选择性BTE抑制剂，最新的体内眼部成像技术，包括 光学相干断层扫描（AS-OCT）和OCT血管造影（OCT-A），以及基因组分析， 免疫组织化学方法。这项拟议中的工作将使我们能够定义BETs在芥末中的作用- 通过表征BD 1和BD 2在角膜损伤中的贡献，阐明了角膜损伤的潜在机制， 机制，并测试BET抑制是否可以有效地治疗急性和延迟损伤。考虑 在开发具有可接受的安全性和前景的BET阻滞剂方面已经报道的成功 在几个I期和II期临床试验中，BET抑制剂可以提供高的转化潜力， 测试并最终用于临床研究。