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

点击翻译按钮获取中文摘要

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.