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（由适用提供）：糖皮质激素（GC）是针对不同炎症性皮肤疾病（包括特应性皮炎和牛皮癣）的最有效且经常使用的抗炎药。不幸的是，用糖皮质激素进行慢性治疗会导致多种有害的副作用，包括皮肤萎缩。那是很大的未满足的需求 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，该转录因子通过复杂机制调节了〜10％的基因组的表达，包括反式激活，这需要GR结合作为基因启动子中GCS反应性元素（GRE）的同型二聚体；通过GR单体与其他转录因子之间的负相互作用介导的反抑制，以及与较低的负阴性和复合物GR的结合。 GR也有非基因组效应。由于对包括皮肤萎缩和高度复杂的细胞类型依赖性GR信号的GC的分子机制缺乏了解，因此新的更安全的GR靶向疗法的发展是相当无效的。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GCS诱导的皮肤萎缩有关的子网络。接下来，我们将采用综合化学组学来鉴定可药物的靶标（萎缩基因）和已建立的化合物（抗原子基因），可以与GC共同给药以改善皮肤萎缩，同时保留GCS的抗炎潜能。最后，我们将使用原代人和小鼠角质形成细胞培养物，人体皮肤等效物（3D筏培养物）以及皮肤萎缩和炎症的小鼠模型进行实验，以验证类固醇诱导的皮肤萎缩的分子驱动因素/促萎缩症，以及对抗催化剂的药物的预测。总体而言，这个高度创新的计划将强烈影响我们对皮肤分子结构的理解。皮肤中主要的分解代谢/合成代谢途径有可能改变GC作为治疗的使用，不仅用于皮肤疾病，而且对于用GC治疗的多种内脏疾病/疾病。此外，可以应用提出的工作的结果，以更好地理解和防止GC的其他萎缩副作用，例如肌肉废物和骨质疏松症，以及具有共享分子签名的其他疾病/条件。