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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.

硫芥子气（SM）是使用最广泛的化学战剂，氮芥子气（NM）是强烷化剂引起DNA损伤以及氧化损伤，导致几种分子途径潜伏期后，它们的作用是炎症反应、表皮细胞死亡，在皮肤组织中产生痛苦的水疱和溃疡，这是主要的靶器官。基于由于暴露剂量和持续时间不同，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。有过多的信息可利用的皮肤病理学后，暴露于起泡剂; 然而，导致急性暴露引起慢性皮肤损伤的复杂分子机制仍然存在，值得商榷我们在SKH-1无毛小鼠中完成的研究表明，急性皮肤起泡剂暴露可导致氧化应激、DNA损伤、信号传导通路的激活和炎性细胞因子的表达。和蛋白水解介质，包括细胞因子，有助于皮肤炎症，水疱形成，延迟伤口愈合。此外，我们还发现NM诱导的MMP-9，炎症，小鼠皮肤中的细胞因子如FGF 2、TNF-α和IL-1β以及VEGF伴随着微 RNA miR-155、miR-203a和miR-21。值得注意的是，这些mi-RNAs与慢性皮肤炎症有关，免疫应答和纤维化（miR-155），通过靶向编码促炎性细胞因子的基因细胞因子如皮肤组织中的TNF-α（miR-203 a）和皮肤伤口愈合和胶原沉积（miR-21）。这个应用程序是建立在这些初步的调查结果，并将详细调查SM和NM的效果暴露于皮肤组织中的miRNA变化。我们的假设是改变的miRNAs与炎症、伤口愈合和纤维化可以靶向基因表达导向分子，途径改变，从而导致由起泡剂暴露引起的慢性皮肤损伤。使用两个NM- 和SM诱导的慢性病变皮肤组织中建立的小鼠皮肤损伤模型，具体目的是：1）确定与炎症、伤口愈合和纤维化相关的miRNA，并分析miRNA靶点，以及相关的分子通路; 2）通过miRNA靶点和通路分析程序，确定与水疱剂诱导的皮肤损伤最相关的miRNA靶分子，并比较结果 NM和SM引起的皮肤损伤之间的关系。预计完成拟议的研究后，鉴定驱动SKH-1无毛小鼠中观察到的分子途径改变的独特miRNA 在SM和NM暴露之后。预计结果将建立miRNA签名，它可以作为新的诊断生物标志物，并开辟了一条新的miRNA靶向治疗途径暴露于SM和NM后的皮肤并发症。