Identification of therapeutic small molecules for treatment of skin fibrosis by modulating epidermal pro-inflammatory signaling

项目摘要/摘要 重新调整药物用途(也称为药物重新定位)比传统药物开发具有优势，因为 它有更短的途径获得FDA的批准，并降低了开发成本。毒品有时会被 通过发现副作用或多重效应而意外地改变用途。近期全面 转录组、蛋白质组和代谢组学分析已经产生了大量的大规模数据。连通性 MAP(Cmap)是一种利用签名匹配来比较唯一转录组的计算方法 特定条件的模式(即签名)。Cmap已被利用于药物的再利用 签名与疾病签名呈反向关系的候选人，表明具有治疗作用 通过逆转与疾病状态相关联的签名来实现潜力。 纤维化指的是一种病理形式的组织修复，其结果是用 无功能疤痕组织，而不是再生功能损伤前组织。特别是，皮肤纤维化是一种 各种皮肤病理的常见结果，包括增生性瘢痕、瘢痕疙瘩和烧伤创面。在……里面 严重的情况下，严重的皮肤纤维化会导致严重的美容毁容、疼痛、行动不便和 难以调节温度。然而，病理性瘢痕的治疗选择是有限的。 粘膜创面愈合速度加快，炎症较少，愈合时疤痕最小。 与皮肤创伤相比。粘膜愈合和皮肤愈合之间的大部分差异是由于 潮湿的粘膜环境。我们显示，通过应用聚亚安酯，闭塞的皮肤伤口 模拟黏膜环境和增强皮肤屏障功能的敷料，愈合更快， 与非闭塞皮肤伤口相比，疤痕较少。对表皮的转录分析显示， 在非闭塞皮肤伤口中的独特特征，我们将其称为减少水合(RH)特征。 我们之前已经证明，抑制表皮中的特定促炎通路 减少真皮的纤维化(增生性疤痕)。我们假设利用预测的小分子 逆转RH信号的Cmap是一种有前景的减少真皮纤维化的策略。我们确认了斯莫尔 使用Cmap预测将逆转RH签名子集的候选分子。我们将验证 小分子在体外减少促炎基因表达和缩小真皮的效果 体内纤维化。有趣的是，我们注意到RH特征和表皮基因之间的相似之处。 皮损性特应性皮炎和银屑病皮肤的表达特征，这也是已知的 表皮屏障功能障碍。因此，这项提案的结果将提供调查的机会。 新的治疗药物，潜在地导致可翻译的方法，不仅缓解症状 纤维化，但也包括由表皮屏障功能损害所驱动或加重的其他病理因素。

Project Summary/Abstract Repurposing of drugs (also called drug repositioning) has advantages over traditional drug development, since it has shorter pathways to FDA approval and reduced development costs. Drugs have sometimes been repurposed serendipitously through discovery of side effects or multiple effects. Recent comprehensive transcriptomic, proteomic, and metabolomic analyses have generated much large-scale data. Connectivity Map (CMap) is a computational approach that utilizes signature matching to compare unique transcriptome patterns (i.e., signatures) of certain conditions. CMap has been harnessed for drug repurposing by selecting candidates whose signatures show inverse relationships with disease signatures, indicating therapeutic potential through reversing the signature associated with a disease state. Fibrosis refers to a pathological form of tissue repair that results in replacement of damaged tissue with nonfunctional scar tissue, rather than regenerating functional pre-injury tissue. In particular, dermal fibrosis is a common outcome of various skin pathologies including hypertrophic scars, keloids, and burn wounds. In serious cases, severe dermal fibrosis can lead to substantial cosmetic disfigurement, pain, loss of mobility, and difficulty regulating temperature. However, therapeutic options for treatment of pathologic scarring are limited. Mucosal wounds undergo accelerated healing, exhibit less inflammation, and heal with minimal scarring compared to cutaneous wounds. Much of the difference between mucosal and cutaneous healing is attributed to the moist mucosal environment. We showed that occluded skin wounds, by application of polyurethane dressings to mimic a mucosal environment and to augment barrier function of the skin, healed faster and with less scarring compared to non-occluded skin wounds. Transcriptomic analysis of the epidermis showed a unique signature in non-occluded skin wounds, which we refer to as the reduced hydration (RH) signature. We have previously demonstrated that inhibition of specific pro-inflammatory pathways in the epidermis reduces fibrosis (hypertrophic scar) in the dermis. We hypothesize that utilizing small molecules predicted by CMap to revert the RH signature is a promising strategy to reduce fibrosis in the dermis. We identified small molecule candidates predicted to reverse subsets of the RH signature using CMap. We will validate the efficacy of small molecules to reduce expression of pro-inflammatory genes in vitro and to reduce dermal fibrosis in vivo. Interestingly, we have noted similarities between the RH signature and epidermal gene expression signatures in lesional atopic dermatitis and psoriatic skin, which are also known to demonstrate epidermal barrier dysfunction. Thus, the outcomes of this proposal will provide opportunities to investigate novel therapeutic drugs, potentially resulting in translatable approaches to alleviate not only symptoms of fibrosis, but also of other pathologies driven or exacerbated by functional impairment of the epidermal barrier.