MicroRNAs in Skin Inflammation and Wounding by Mustard Vesicants.

MicroRNA 在皮肤炎症和芥末出疱剂造成的损伤中的作用。

基本信息

批准号：
9974481
负责人：
Rajesh Agarwal
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974481
关键词：
Acute Affect Alkylating Agents Automobile Driving Bulla Cell Death Chemical Warfare Agents Chronic Collagen Complex Conditioned Reflex Cutaneous Cytokine Signaling DNA Damage Data Deposition Dose Erythema Exposure to FGF2 gene Fibrosis Gene Expression Genes Immune response Impaired wound healing Inbred HRS Mice Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukins Lead Lesion Mechlorethamine Mediator of activation protein Medical MicroRNAs Modeling Molecular Mus Mustard Mustard Gas Organ Outcome Oxidative Stress Pathology Pathway Analysis Pathway interactions Pigmentation physiologic function Population Quality of life RNA Reporting Role Scheme Signal Pathway Skin Skin Tissue Skin injury Skin wound healing TNF gene Ulcer Untranslated RNA Vascular Endothelial Growth Factors Vesicants base cytokine design diagnostic biomarker novel diagnostics novel marker oxidative damage programs response skin disorder skin lesion targeted treatment wound wound healing

项目摘要

Sulfur mustard (SM), the most widely used chemical warfare agent, and nitrogen mustard (NM) are strong alkylating agents causing DNA damage as well as oxidative damage leading to the activation of several molecular pathways. After a latent period, their effect is an inflammatory response, epidermal cell death and excruciating vesication and ulcerations in the skin tissue, which is the main target organ. Based on the exposure dose and duration, these effects can lead to long-term skin complications like xerosis, erythema and pigmentation changes with a long wound healing tenure causing medical burden and affecting the life quality. There is plethora of information available on the skin pathology following exposure to vesicating agents; however, the complex molecular mechanisms that lead to chronic skin lesions from acute exposures are still debatable. Our completed studies in SKH-1 hairless mice have shown that acute cutaneous vesicant exposure can lead to oxidative stress, DNA damage, activation of signaling pathways, and expression of inflammatory and proteolytic mediators including cytokines, contributing to the skin inflammation, blister formation, and delayed wound healing. Furthermore, we also found that NM-induced changes in MMP-9, inflammatory cytokines like FGF2, TNF-α and IL-1β and VEGF in mouse skin were accompanied with alterations in micro- RNAs miR-155, miR-203a and miR-21. Notably, these mi-RNAs are connected to chronic skin inflammation, immune response and fibrosis (miR-155), cytokine signaling by targeting genes encoding pro-inflammatory cytokines like TNF-α in the skin tissue (miR-203a) and skin wound healing and collagen deposition (miR-21). This application is built upon these preliminary findings, and will investigate in detail the effect of SM and NM exposure on miRNA changes in the skin tissue. Our hypothesis is that altered miRNAs related to inflammation, wound healing and fibrosis could target the gene expression directing molecular pathway alterations to cause chronic skin injury from vesicating agents’ exposure. Employing both NM- and SM-induced skin tissues with chronic lesions in established mouse skin injury models, specific aims are: 1) to determine miRNAs associated with inflammation, wound healing and fibrosis, and analyze miRNA targets as well as related molecular pathways via miRNA target and pathway analysis programs; and 2) to confirm the identified miRNA target molecules most relevant to vesicant-induced skin injury, and compare the outcomes between both the NM- and SM-induced skin injuries. Completion of the proposed studies is anticipated to identify unique miRNAs driving the molecular pathway alterations observed in SKH-1 hairless mice following both SM- and NM-exposures. Outcomes are anticipated to establish miRNA signatures, which can serve as novel diagnostic biomarkers and open a new avenue of miRNA-targeted treatment of skin complications following SM and NM exposure.

使用最广泛的化学战剂硫芥（SM）和氮芥（NM）的毒性很强烷化剂会造成 DNA 损伤以及氧化损伤，从而导致多种活性物质的激活潜伏期后，它们的作用是炎症反应、表皮细胞死亡和皮肤组织出现令人难以忍受的起泡和溃疡，这是主要的靶器官。暴露剂量和持续时间，这些影响可能导致长期皮肤并发症，如干燥症、红斑和色素沉着随着伤口愈合时间的延长而改变，造成医疗负担并影响生活质量。有大量关于接触起泡剂后皮肤病理学的信息；然而，由于急性暴露而导致慢性皮肤损伤的复杂分子机制仍然未知。我们在 SKH-1 无毛小鼠中完成的研究表明，急性皮肤起疱剂暴露是有争议的。可导致氧化应激、DNA 损伤、信号通路激活和炎症表达和蛋白水解介质，包括细胞因子，导致皮肤炎症、水疱形成和此外，我们还发现 NM 诱导 MMP-9、炎症的变化。小鼠皮肤中的 FGF2、TNF-α、IL-1β 和 VEGF 等细胞因子伴随着微 RNA miR-155、miR-203a 和 miR-21 值得注意的是，这些 miRNA 与慢性皮肤炎症有关。免疫反应和纤维化 (miR-155)，通过靶向编码促炎基因的细胞因子信号转导皮肤组织中的细胞因子如 TNF-α (miR-203a) 以及皮肤伤口愈合和胶原蛋白沉积 (miR-21)。该应用程序建立在这些初步发现的基础上，并将详细研究 SM 和 NM 的效果我们的假设是 miRNA 与皮肤组织中的 miRNA 变化有关。炎症、伤口愈合和纤维化可以靶向基因表达指导分子使用 NM- 导致慢性皮肤损伤的途径改变。以及在已建立的小鼠皮肤损伤模型中SM诱导的皮肤组织出现慢性病变，具体目标是：1）确定与炎症、伤口愈合和纤维化相关的 miRNA，并分析 miRNA 靶标以及通过 miRNA 靶标和通路分析程序确定相关分子通路；2) 确认确定了与起疱剂引起的皮肤损伤最相关的 miRNA 靶分子，并比较了结果 NM 和 SM 引起的皮肤损伤之间的关系预计将完成拟议的研究。鉴定驱动 SKH-1 无毛小鼠中观察到的分子通路改变的独特 miRNA SM 和 NM 暴露后的结果预计会建立 miRNA 特征，可以作为新型诊断生物标志物并开辟 miRNA 靶向治疗的新途径 SM 和 NM 暴露后的皮肤并发症。