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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

基本信息

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
项目类别：
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

项目摘要

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.

主要表观遗传调控因子在眼化学损伤中的作用