Project 3: Intercepting Renal Damage following Skin Exposure to Arsenicals

项目 3：阻止皮肤接触砷剂后的肾损伤

• 批准号: 10249115
• 负责人: ANUPAM AGARWAL
• 金额: $ 57.53万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249115
• 关键词: Acetylation; Acute; Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Animals; Antidotes; Apoptosis; Arsenicals; Biological Markers; Blood capillaries; Bromodomain; Bulla; Categories; Centers of Research Excellence; Chemical Injury; Chemical Weapons; Chemicals; Cutaneous; Data; Dependence; Dose; Enzymes; Epigenetic Process; Exposure to; Extravasation; FDA approved; Family member; Fibrosis; Genes; Genetic; Genetic Transcription; Goals; Heme; Hemeproteins; Histone Acetylation; Histones; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Intercept; Intervention; Kidney; Kinetics; Knockout Mice; Lead; Lung; Lysine; Mediating; Microscopic; Modification; Molecular; Molecular Target; Morbidity - disease rate; Organ; Oxides; Pathway interactions; Pharmacology; Plasma Proteins; Promoter Regions; Property; Protein Acetylation; Protein Family; Proteins; Research; Research Personnel; Role; Shock; Signal Transduction; Skin; Skin Manifestations; Skin injury; Structure; Therapeutic Intervention; Time; Tissues; Toxic effect; Up-Regulation; Work; World War I; attenuation; base; epigenetic regulation; heme oxygenase-1; lewisite; lung injury; member; molecular drug target; mortality; mouse model; multiorgan injury; novel; novel therapeutic intervention; oxidative damage; recruit; renal damage; response; skin damage; skin lesion; small molecule; synergism; targeted treatment; therapeutic target; tool

Arsenicals are an important category of chemical weapons due to their devastating effects on the skin as well as systemic effects damaging multiple organs including the kidney and lung. This project is based on our findings that cutaneous exposure to lewisite, an arsenical first synthesized during world war I, not only damages skin but is also rapidly absorbed and exerts toxic effects in the kidney leading to both acute and delayed kidney damage. Preliminary studies demonstrate that arsenicals cause epigenetic histone remodeling by hyperacetylation and recruitment of BRD4 to promoter regions of inducible genes associated with inflammation and tissue damage. BRD4 is a member of the bromo- and extra-terminal domain family of proteins. In addition, we observed marked upregulation of the cytoprotective protein, heme oxygenase-1 (HO- 1) in the kidney following topical exposure to lewisite. Arsenicals induce higher expression of BRD4 and inflammatory signaling genes in HO-1 knockout mice as compared to wild-type littermates, suggesting the importance of HO-1 in epigenetic regulation of inflammatory responses. Taken together, these studies underscore the significance of both acute and delayed kidney damage following a single cutaneous arsenical exposure and identify two potential inter-related molecular targets, BRD4 and HO-1 in renal injury. The overall goal of this project is to develop mechanism-based post-exposure countermeasures that can mitigate arsenical-induced kidney damage. Our hypothesis is that toxic doses of arsenicals cause acetylation of proteins (histones) and subsequent recruitment of bromodomain proteins resulting in activation of injury pathways and that blocking bromodomain signaling or its downstream effectors can mitigate kidney injury. In Aim 1, an arsenical mediated murine model of AKI will be characterized to determine the dose- and time-dependence of kidney damage. In Aim 2, we determine the mechanisms by which arsenicals cause AKI focusing on BRD4 and HO-1 for intervention in arsenicals-induced AKI. In Aim 3, we will develop targeted therapeutic intervention in arsenical-induced AKI to determine the optimal window for the beneficial effects by post-exposure treatment in animals exposed to arsenicals. Both FDA approved and novel small molecules will be assessed in this aim. Successful completion of our research as proposed here will not only provide an effective antidote for chemical injury but will also contribute to a broader understanding of how endogenous epigenetic responses can be exploited towards developing new therapeutic strategies for AKI.

砷剂是化学武器的一个重要类别，因为它们对皮肤也有破坏性影响 作为系统性影响损害多个器官，包括肾脏和肺。这个项目是基于我们的 研究发现，皮肤接触路易氏剂，一种在第一次世界大战期间首次合成的砷，不仅 损害皮肤，但也被迅速吸收，并在肾脏中产生毒性作用，导致急性和 延迟性肾损伤初步研究表明，砷剂引起表观遗传组蛋白重塑 通过BRD 4的超乙酰化和募集到与以下相关的诱导基因的启动子区域， 炎症和组织损伤。BRD 4是BRD 4的溴-和额外-末端结构域家族的成员。 proteins.此外，我们观察到细胞保护蛋白血红素氧合酶-1（HO-1）的显著上调。 1)在肾脏中的作用。砷剂诱导BRD 4的更高表达， HO-1基因敲除小鼠与野生型同窝小鼠相比，炎症信号基因的表达水平降低，表明HO-1基因敲除小鼠的炎症信号基因表达水平降低。 HO-1在炎症反应表观遗传调控中的重要性。综合来看，这些研究 强调急性和迟发性肾损害的意义后，单一的皮肤砷 暴露和确定两个潜在的相互关联的分子靶点，BRD 4和HO-1在肾损伤中。 该项目的总体目标是制定基于机制的暴露后对策， 可以减轻砷引起的肾损伤。我们的假设是，有毒剂量的砷会导致 蛋白质（组蛋白）的乙酰化和随后的溴结构域蛋白的募集导致激活 阻断布罗莫结构域信号传导或其下游效应物可以减轻肾脏损伤， 损伤在目标1中，将对砷介导的阿基小鼠模型进行表征以确定剂量和 肾损害的时间依赖性。在目标2中，我们确定砷剂引起阿基的机制 重点关注BRD 4和HO-1，用于干预砷诱导的阿基。在目标3中，我们将制定有针对性的 对砷诱导的阿基进行治疗性干预，以确定有益效果的最佳窗口， 对接触砷剂的动物进行接触后治疗。FDA批准的新型小分子将 在这个目标上进行评估。成功完成我们在这里提出的研究不仅将提供一个 有效的解毒剂，但也将有助于更广泛地了解如何内源性 表观遗传反应可用于开发阿基的新治疗策略。