Integrative informatics approach to develop safe glucocorticoid therapies

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 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.