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: 9223338
• 负责人: Irina Budunova
• 金额: $ 10万
• 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/9223338
• 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; Dermatology; Dermis; Development; Disease; Epidermis; Fatty acid glycerol esters; Genes; Genome; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Homo; Human; Indium; Industry; Inflammation; Inflammatory; Informatics; Ligands; Maps; Mediating; Molecular; Molecular Profiling; 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; Weight; Work; Wound Infection; cell type; chronic inflammatory skin; dimer; in vivo; inhibitor/antagonist; innovation; keratinocyte; mTOR Inhibitor; monomer; mouse model; non-genomic; novel; prevent; programs; promoter; receptor binding; research study; response; skin disorder; skin morphogenesis; 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）是治疗不同炎症性皮肤病（包括特应性皮炎和牛皮癣）最有效和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) - GC 的靶向抗炎疗法由 GR 介导，GR 是一种转录因子，通过复杂机制（包括反式激活）调节约 10% 的基因组表达，这需要 GR 作为同源二聚体结合。基因启动子中的 GC 响应元件 (GRE)，通过 GR 单体和其他转录因子之间的负相互作用介导，并且 GR 与不太保守的负和复合因子结合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，因此开发了新的更安全的 GR 靶向疗法。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。药物靶标（萎缩基因）和既定化合物（抗萎缩基因）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，我们将使用原代人和小鼠角质形成细胞培养物进行实验，人类皮肤等效物（3D 筏培养）和皮肤萎缩和炎症的小鼠模型，以验证类固醇引起的皮肤萎缩的分子驱动因素/萎缩基因和药物再利用总体而言，这一高度创新的计划将极大地影响我们对皮肤主要分解代谢/合成代谢途径的理解，并有可能改变 GC 的治疗用途，不仅适用于皮肤疾病，而且有可能改变 GC 的治疗方法。此外，拟议工作的结果还可用于更好地了解和预防 GC 的其他萎缩性副作用，例如肌肉浪费和骨质疏松症。与具有共同分子特征的其他疾病/病症一样。