Unraveling the corneal and retinal mechanisms of chemical injury
揭示化学损伤的角膜和视网膜机制
基本信息
- 批准号:10882069
- 负责人:
- 金额:$ 49.82万
- 依托单位:
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementAcuteAlkaliesAnteriorApplications GrantsArginine deiminaseAutomobile DrivingBindingBlindnessCalciumCell Culture TechniquesCell DeathCharacteristicsChemical ExposureChemical InjuryChronicCicatrixClinicClinicalCorneaCorneal UlcerCorneal painCutaneousDNA DamageDataDiseaseDoseDrug CombinationsDrug TargetingEnzymesEpithelial CellsEventEvolutionExposure toEyeEye InjuriesEye diseasesFibrosisFundingFutureGeneticGliosisGrantHumanIn VitroInfection preventionInflammationInjuryIntermediate Filament ProteinsInvestigationKnockout MiceLaser injuryLinkMechlorethamineMediatingMediatorMedicalModelingModificationMolecularMuller&aposs cellMusMustard GasOcular PathologyOryctolagus cuniculusOxidesPathologicPathologyPathway interactionsPharmaceutical PreparationsPoisonPost-Translational Protein ProcessingProtein IsoformsProteinsProteomicsPublishingRattusReportingResearchRetinaRetinal DegenerationSecuritySeveritiesSulfurSystemTP53 geneTestingTherapeuticTissuesTranslatingVesicantsVisual impairmentanalogbiological adaptation to stresscellular targetingchemical countermeasurechemical threatcombatcorneal epitheliumcrosslinkdrug discoveryexperimental studyhuman diseasein vivoin vivo Modelinhibitorinjuredlewisitelung injurymass casualtynovelpharmacologicprogramsresponsesymptom managementweapons
项目摘要
Abstract:
Chemical threat agents can potentially be weaponized to cause mass casualties and such
egregious events are of grave concern to homeland security. Sulfur mustard and its analog
nitrogen mustard (NM) are vesicants that cause severe acute injury to ocular tissues and
ultimately develop fibrotic scarring leading to vision loss. As medical treatments for vesicant injury
have yet to be developed for paucity of a complete understanding of their pathophysiological
mechanisms, this unmet medical need remains an urgent matter of importance to the Chemical
Countermeasures Research Program (CCRP). Under an exploratory R21 grant funded by the
CCRP, we have discovered that NM injury to the mouse cornea triggers a rapid and profound
induction of retinal gliosis. This retinal response is coordinated in reactive Muller glia with
activation of the posttranslational modification (PTM) known as citrullination. This finding extends
our prior results showing that retinal hypercitrullination driven by the enzyme peptidyl arginine
deiminase (PAD)-4 is a shared pathological feature that is common to a number of different injury
and disease paradigms. But critical gaps remain regarding the molecular steps involved in the
PAD-hypercitrullination axis. As other published reports have shown that NM crosslinks tumor
suppressor p53 and the p53 DNA damage pathway interacts with PAD4, these data provokes an
interesting idea whether these two major orchestrators of pathological response are tied to
activating hypercitrullination in both the cornea and retina. In this R01 grant proposal, we will
investigate the acute and chronic (delayed) injury mechanisms of NM across the cornea and retina
in mouse and rat models. Specifically in Aim 1, we will investigate the molecular mechanisms of
the p53-PAD axis involving corneal hypercitrullination and identify the relevant PAD using both in
vivo and cell culture models to study NM injury. In Aim 2, we will characterize the corneal and
retinal citrullinomes of NM injury using proteomics by examining the temporal changes over the
early and chronic stages. This study will allow us to identify key PAD substrates of acute and
chronic injury states, permitting us to decipher the evolution of key protein players modified by
citrullination in perpetuating corneal and retinal pathology. We believe this in-depth investigation
into hypercitrullination in the NM injured eye could unravel novel mechanisms and druggable PAD
targets that would be critical for drug discovery to combat chemical injury to the human eye. Given
that PADs are already being investigated as targets for several common diseases, the likelihood
of clinical drugs becoming available for humans in the near future makes this an attractive target
class for further mechanistic assessment.
摘要:
化学威胁剂有可能被武器化,造成大规模伤亡,
令人震惊的事件是国土安全的严重关切。硫芥及其类似物
氮芥(NM)是引起眼组织严重急性损伤的水疱剂,
最终形成纤维化瘢痕,导致视力丧失。作为治疗水疱性损伤的药物
由于缺乏对其病理生理学的完整理解,
尽管有各种机制,但这一未得到满足的医疗需求仍然是化学品管理局的一个紧迫的重要事项。
对策研究计划(CCRP)。根据由联合国资助的探索性R21赠款,
CCRP,我们已经发现,NM损伤小鼠角膜触发了快速和深刻的
诱导视网膜神经胶质增生。这种视网膜反应在反应性Muller神经胶质细胞中协调,
翻译后修饰(PTM)的激活,称为瓜氨酸。这一发现延伸到
我们先前的研究结果表明,由肽基精氨酸酶驱动的视网膜高瓜氨酸血症
脱亚胺酶(PAD)-4是许多不同损伤共有的病理特征
和疾病模式。但关键的差距仍然涉及的分子步骤,
PAD-高瓜氨酸轴。正如其他已发表的报告表明,NM交联肿瘤
p53和p53 DNA损伤通路与PAD 4相互作用,这些数据引起了对PAD 4的研究。
有趣的想法是,这两个主要的病理反应是否与
激活角膜和视网膜中的高瓜氨酸酶。在此R 01赠款提案中,我们将
研究NM对角膜和视网膜的急性和慢性(延迟)损伤机制
在小鼠和大鼠模型中。特别是在目标1中,我们将研究
涉及角膜高瓜氨酸血症的p53-PAD轴,
体内和细胞培养模型来研究NM损伤。在目标2中,我们将表征角膜和
视网膜瓜氨酸组的NM损伤使用蛋白质组学通过检查时间的变化,
早期和慢性阶段。这项研究将使我们能够确定急性和慢性炎症的关键PAD底物,
慢性损伤状态,使我们能够破译关键蛋白质的进化,
瓜氨酸可使角膜和视网膜病变永久化。我们相信这次深入调查
在NM受伤的眼睛中转化为高瓜氨酸可以揭示新的机制和可药物化的PAD
这些目标对于药物发现至关重要,以对抗对人眼的化学损伤。给定
PAD已经被研究为几种常见疾病的靶点,
在不久的将来,临床药物将可用于人类,这使其成为一个有吸引力的目标。
进一步机械评估。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROYCE MOHAN其他文献
ROYCE MOHAN的其他文献
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{{ truncateString('ROYCE MOHAN', 18)}}的其他基金
Targeting Citrullination in Ocular Chemical Injury
针对眼部化学损伤的瓜氨酸化
- 批准号:
10206486 - 财政年份:2021
- 资助金额:
$ 49.82万 - 项目类别:
Targeting Citrullination in Ocular Chemical Injury
针对眼部化学损伤的瓜氨酸化
- 批准号:
10459390 - 财政年份:2021
- 资助金额:
$ 49.82万 - 项目类别:
Targeting Citrullination in Ocular Chemical Injury
针对眼部化学损伤的瓜氨酸化
- 批准号:
10516386 - 财政年份:2021
- 资助金额:
$ 49.82万 - 项目类别:
Targeting Citrullination in Ocular Chemical Injury
针对眼部化学损伤的瓜氨酸化
- 批准号:
10705952 - 财政年份:2021
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$ 49.82万 - 项目类别:
Novel Modular Vascular Patterning Assay for HTS
HTS 的新型模块化血管模式分析
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7648164 - 财政年份:2008
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7527007 - 财政年份:2008
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HTS 的新型模块化血管模式分析
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8243126 - 财政年份:2008
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