Integrative informatics approach to develop safe glucocorticoid therapies

开发安全糖皮质激素疗法的综合信息学方法

• 批准号: 9265107
• 负责人: Irina Budunova
• 金额: $ 48.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265107
• 关键词: Academia; Adult; Adverse effects; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Atopic Dermatitis; Atrophic; Atrophic condition of skin; Biology; Cell Culture Techniques; Chemicals; Child; Chronic; Clinical; Complex; Computing Methodologies; Contusions; Cosmetics; Cutaneous; DNA Damage; Dermatologic; Dermatology; Dermis; Development; Disease; Elements; Epidermis; Fatty acid glycerol esters; Genes; Genome; Glucocorticoid Receptor; Glucocorticoids; Goals; Human; Industry; Inflammation; Inflammatory; Informatics; Ligands; Maps; Mediating; Molecular; Molecular Profiling; Morphogenesis; Mus; Muscular Atrophy; Osteoporosis; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Psoriasis; Quality of life; Receptor Signaling; Resistance; Risk; Sirolimus; Site; Skin; Stem cells; Steroids; Testing; Therapeutic Effect; Thick; Transactivation; United States; Visceral; Work; Wound Infection; cell type; chronic inflammatory skin; experimental study; glucocorticoid receptor alpha; in vivo; inhibitor/antagonist; innovation; keratinocyte; mTOR Inhibitor; monomer; mouse model; non-genomic; novel; prevent; programs; promoter; public health relevance; receptor binding; response; skin disorder; subcutaneous; targeted treatment; transcription factor; transcriptome sequencing

 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.

 描述（由申请人提供）：糖皮质激素（GC）是治疗特应性皮炎和牛皮癣等不同炎症性皮肤病最有效且最常用的抗炎药物之一。不幸的是，长期使用糖皮质激素治疗会导致多种有害副作用，包括皮肤萎缩。因此，存在大量未满足的需求 新型更安全的糖皮质激素受体（GR）——靶向抗炎疗法。 GC 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约 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 GC 响应元件 (GRE) 结合；反式抑制，通过 GR 单体和其他转录因子之间的负相互作用介导，以及 GR 与不太保守的负向和复合 GRE 结合。 GR 还存在非基因组效应。由于缺乏对 GC 副作用（包括皮肤萎缩）和高度复杂的细胞类型依赖性 GR 信号传导的分子机制的了解，新的更安全的 GR 靶向疗法的开发效率相当低。我们建议使用网络生物学方法来构建和分析皮肤中GC诱导的复杂分子网络，以及与GC诱导的皮肤萎缩相关的子网络。接下来，我们将采用综合化学基因组学来识别可药物靶标（萎缩基因）和已确定的化合物（抗萎缩基因），这些化合物可以与 GC 共同给药，以改善皮肤萎缩，同时保留 GC 的抗炎潜力。最后，我们将使用原代人类和小鼠角质形成细胞培养物、人类皮肤等效物（3D 筏培养物）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/萎缩基因，以及抗萎缩基因的药物再利用预测。 总的来说，这个高度创新的项目将强烈影响我们对皮肤分子结构的理解； GC 治疗皮肤中主要的分解代谢/合成代谢途径，有可能改变 GC 的治疗用途，不仅适用于皮肤疾病，还适用于用 GC 治疗的各种内脏疾病/病症。此外，拟议工作的结果可用于更好地理解和预防GC的其他萎缩性副作用，例如肌肉浪费和骨质疏松症，以及具有共同分子特征的其他疾病/病症。