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.

主要表观遗传调节因子在眼化学损伤中的作用 摘要 芥末发泡剂包括硫芥末(SM)和氮芥末(NM)，会引起严重的呼吸道、皮肤、 和眼部受伤。它们在战争中被用作化学武器，也有可能 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 普遍存在于接触SM的受害者中。炎症、新生血管和纤维化是三大问题和 球员在芥末诱导的角膜损伤，但其潜在的机制很大程度上是未知的，这限制了 制定有效的疾病管理办法。BET(溴域和末端外) 结构域)家族蛋白，包括普遍表达的BRD2、BRD3和BRD4以及睾丸特异的BRDT 表观遗传的读者。它们识别并结合N端突出尾部的乙酰化赖氨酸(KAc) 从核小体的组蛋白核心，并作为支架蛋白招募转录因子和 正转录延伸因子b(P-TEFb)复合体，磷酸化并释放暂停的RNA 聚合酶II(RNAPII)转录转录因子靶向基因。这些赌注起到了关键作用 炎症、新生血管和纤维化在许多疾病中都有，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，表明打赌在角膜芥末伤中起着关键作用。 并提出进一步探索这一新的机制。我们将检验NM损伤导致的假设 角膜炎症、新生血管和纤维化通过激活主要的表观遗传调节基因 小鼠和兔模型，选择性BTE抑制剂，体内最先进的眼部成像技术，包括 光学相干断层扫描(AS-OCT)和OCT-血管成像(OCT-A)，以及基因组图谱和 免疫组织化学方法。拟议的工作将使我们能够定义投注在芥末中的作用- 通过表征BD1和BD2在角膜损伤中的作用来诱导损伤，阐明潜在的 机制，以及BET抑制是否能有效治疗急性和迟发性损伤。考虑 已报道的BET阻滞剂的成功开发具有可接受的安全性和前景 在几个I期和II期临床试验中，BET抑制剂可能提供高翻译潜力 经过测试并最终用于临床研究。