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

项目总结/摘要 药物再利用（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。毒品有时候 通过发现副作用或多种作用偶然地重新利用。近期综合 转录组学、蛋白质组学和代谢组学分析已经产生了许多大规模的数据。连接 Map（CMap）是一种利用特征匹配来比较独特转录组的计算方法 模式（即，签名）的某些条件。CMap已被用于药物再利用， 其特征与疾病特征呈反比关系的候选者，指示治疗性 通过逆转与疾病状态相关的签名来实现潜在的治疗。 纤维化是指组织修复的病理形式，其导致受损组织被替换为 非功能性疤痕组织，而不是再生功能性损伤前组织。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。在 严重的情况下，严重的真皮纤维化可导致大量的美容缺陷，疼痛，丧失活动能力， 难以调节温度。然而，用于治疗病理性瘢痕形成的治疗选择是有限的。 粘液性伤口加速愈合，炎症较少，愈合后瘢痕最小 与皮肤伤口相比。粘膜愈合和皮肤愈合之间的大部分差异归因于 潮湿的粘膜环境。我们发现，通过应用聚氨酯， 敷料模拟粘膜环境并增强皮肤的屏障功能，愈合更快， 与非封闭性皮肤伤口相比，疤痕较少。表皮的转录组学分析显示， 在非封闭性皮肤伤口中的独特特征，我们将其称为水合作用减少（RH）特征。 我们以前已经证明，抑制表皮中特定的促炎途径， 减少真皮纤维化（增生性瘢痕）。我们假设，利用小分子预测， 逆转RH特征的CMap是减少真皮纤维化的有希望的策略。我们发现小 使用CMap预测逆转RH特征子集的候选分子。我们将验证 小分子在体外减少促炎基因表达和减少皮肤炎症的功效 体内纤维化。有趣的是，我们注意到RH信号和表皮基因之间的相似性， 在损伤性特应性皮炎和银屑病皮肤中的表达特征，其也已知证实了 表皮屏障功能障碍因此，本提案的结果将提供调查的机会， 新的治疗药物，可能导致翻译的方法，以减轻不仅症状， 纤维化，而且还包括由表皮屏障的功能损害驱动或加剧的其他病理。

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.