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

基本信息

批准号：
9767161
负责人：
ANUPAM AGARWAL
金额：
$ 56.48万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9767161
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 Structure Therapeutic Intervention Time Tissues Toxic effect Up-Regulation Work World War I attenuation base epigenetic regulation heme oxygenase-1 lewisite member molecular drug target mortality mouse model multiorgan injury novel novel therapeutic intervention recruit renal damage response skin lesion small molecule synergism targeted treatment therapeutic target tool

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 Structure Therapeutic Intervention Time Tissues Toxic effect Up-Regulation Work World War I attenuation base epigenetic regulation heme oxygenase-1 lewisite member molecular drug target mortality mouse model multiorgan injury novel novel therapeutic intervention recruit renal damage response skin lesion small molecule synergism targeted treatment therapeutic target tool

展开

项目摘要

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.

砷也是化学武器的重要类别，因为它们对皮肤的毁灭性影响也是随着系统性效应破坏包括肾脏和肺在内的多个器官。这个项目是基于我们的皮肤暴露于Lewisite的发现，这是第一次世界大战期间首次合成的砷损害皮肤，但也迅速吸收并在肾脏中发挥有毒作用，导致急性和延迟肾脏损伤。初步研究表明，砷引起表观遗传组蛋白重塑通过对与诱导基因的启动子区域的高乙酰化和募集炎症和组织损伤。 BRD4是Bromo和末端域家族的成员蛋白质。此外，我们观察到细胞保护蛋白血红素氧酶-1的明显上调（ho- 1）在局部暴露于路易斯特岩之后的肾脏中。砷诱导BRD4和与野生型同窝仔相比，HO-1基因敲除小鼠的炎症信号传导基因，表明 HO-1在炎症反应的表观遗传调节中的重要性。总之，这些研究在单一皮肤砷之后，强调了急性和延迟肾脏损伤的重要性暴露并确定两个潜在相关的分子靶标，即肾损伤中的BRD4和HO-1。该项目的总体目标是开发基于机制的暴露后对策可以减轻砷引起的肾脏损伤。我们的假设是毒毒剂量的原因蛋白质（组蛋白）的乙酰化以及随后募集溴脱域蛋白，导致激活伤害途径以及阻塞溴ab域信号传导或其下游效应子可以减轻肾脏受伤。在AIM 1中，将对AKI的砷介导的鼠模型进行表征，以确定剂量和剂量肾脏损伤的时间依赖性。在AIM 2中，我们确定砷引起AKI的机制专注于BRD4和HO-1，以干预砷引起的AKI。在AIM 3中，我们将发展目标对砷引起的AKI进行治疗干预，以确定最佳的窗口暴露于砷的动物的暴露后治疗。 FDA批准和新颖的小分子都将在此目标中得到评估。在这里提出的成功完成我们的研究不仅会提供有效的化学损伤解毒剂，但也将有助于更广泛地了解内源性可以利用表观遗传学反应来为AKI制定新的治疗策略。