The Journal of clinical investigation
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The transmission of pruritoceptive (itch) messages involves specific neural circuits within the spinal cord that are distinct from those that transmit pain messages. These itch-specific circuits are tonically regulated by inhibitory interneurons in the dorsal horn. Consistent with these findings, it has previously been reported that loss of GABAergic interneurons in mice harboring a deletion of the transcription factor Bhlhb5 generates a severe, nonremitting condition of chronic itch. ⋯ BHLHB5-deficient mice that received transplants demonstrated a substantial reduction of excessive scratching and dramatic resolution of skin lesions. In contrast, the scratching persisted and skin lesions worsened over time in sham-treated mice. Together, these results indicate that cell-mediated restoration of inhibitory controls has potential as a powerful, cell-based therapy for neuropathic itch that not only ameliorates symptoms of chronic itch, but also may modify disease.
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Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. ⋯ In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.