Integrative informatics approach to develop safe glucocorticoid therapies

 描述(申请人提供)：糖皮质激素(GC)是最有效和最常用的抗炎药物之一，用于治疗不同的炎症性皮肤病，包括特应性皮炎和牛皮癣。不幸的是，长期使用糖皮质激素治疗会导致多种不良副作用，包括皮肤萎缩。因此，有大量未得到满足的需求 新的更安全的糖皮质激素受体(GR)靶向抗炎疗法。GCs的作用是由GR介导的，GR是一种转录因子，通过复杂的机制调节~10%的基因组表达，包括反式激活，这需要GR作为同源二聚体与基因启动子中的GCs反应元件(GRE)结合；反式抑制，通过GR单体与其他转录因子之间的负相互作用介导；以及GR与保守性较低的负GRE和复合GRE的结合。GR也有非基因组效应。由于缺乏对GCs副作用的分子机制的了解，包括皮肤萎缩和高度复杂的细胞类型依赖的GR信号，因此开发更安全的GR靶向治疗是相当低效的。我们建议使用网络生物学的方法来构建和分析GCs在皮肤中诱导的复杂分子网络，以及与GCs诱导的皮肤萎缩相关的子网络。接下来，我们将使用综合化学基因组学来确定可用药的靶点(萎缩原)和已建立的化合物(抗萎缩原)，这些化合物可以与GC共同给药来改善皮肤萎缩，同时保留GC的抗炎潜力。最后，我们将使用原代培养的人和小鼠角质形成细胞、人类皮肤的等效物(3D RAFT培养)和小鼠皮肤萎缩和炎症模型进行实验，以验证类固醇诱导的皮肤萎缩的分子驱动因素/萎缩成因，以及抗萎缩成因的药物再用途预测。总体而言，这一高度创新的计划将极大地影响我们对皮肤分子结构的理解；皮肤中主要的分解代谢/合成代谢途径，并有可能改变GC作为治疗方法的使用，不仅用于皮肤病，还用于使用GC治疗各种内脏疾病/紊乱。此外，拟议工作的结果可用于更好地了解和预防GCs的其他萎缩副作用，如肌肉废物和骨质疏松症，以及具有共同分子特征的其他疾病/状况。

 DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are among the most effective and frequently used anti-inflammatory drugs for different inflammatory skin diseases including atopic dermatitis and psoriasis. Unfortunately, chronic treatment with glucocorticoids results in multiple deleterious side effects including skin atrophy. Thus, there is significant unmet need for novel safer glucocorticoid receptor (GR) - targeted anti-inflammatory therapies. Effects of GCs are mediated by GR, a transcription factor that modulates expression of ~ 10% of genome via complex mechanisms, including transactivation, which requires GR binding as a homo-dimer to GCs-responsive elements (GRE) in gene promoters; transrepression, mediated via negative interaction between GR monomer and other transcription factors, and GR binding to less conserved negative and composite GREs. There are also non-genomic effects of GR. Due to the lack of understanding of molecular mechanisms underlying side effects of GCs including skin atrophy, and highly complex cell type-dependent GR signaling, the development of new safer GR-targeted therapies was rather inefficient. We propose to use network biology approach to construct and analyze complex molecular networks induced by GCs in skin, and sub-networks related to GCs- induced skin atrophy. Next, we will employ an integrative chemogenomics to identify druggable targets (atrophogenes) and established compounds (anti-atrophogenes) that could work in co-administration with GCs to ameliorate skin atrophy while preserving anti-inflammatory potential of GCs. Finally, we will conduct experiments using primary human and mouse keratinocyte cell cultures, human skin equivalents (3D raft cultures), and mouse models of skin atrophy and inflammation to validate molecular drivers/atrophogenes of steroid-induced skin atrophy, and drug repurposing predictions for anti-atrophogenes. Overall, this highly innovative program will strongly impact our understanding of molecular architecture of the skin; major catabolic/anabolic pathways in skin and has the potential to transform the use of GCs as therapy, not only for cutaneous diseases but also for the wide range of visceral diseases/disorders treated with GCs. In addition, the results of proposed work could be applied to better understand and prevent other atrophic side effects of GCs such as muscle waste and osteoporosis, as well as other diseases/conditions with shared molecular signature.