Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pathway-specific markers. We demonstrate that BMPR-II in flow cytometrically characterised white blood cell subsets is reduced in a proportion of patients, however proteomic analysis demonstrates pleiotropic alterations of TGFb/BMP modulators. Downstream BMPR-II canonical and non-canonical signalling is impacted and measurable in whole blood. We present discovery and international replication cohorts for a transcriptomic BMPR-II signalling signature. The composite biomarker panel is repeatable, reproducible, longitudinally stable and expressed in correlated gene modules in PAH which associate with clinical outcomes. The assay performance characteristics of the biomarker panel make it feasible for early phase, target engagement clinical trials and an adaptive three arm study of two pre-clinically validated modulators of BMPR-II is underway.
Real-Time Segmentation and Classification of Birdsong Syllables for Learning Experiments
Songbirds are essential animal models for studying neuronal and behavioral mechanisms of learned vocalizations. Bengalese finch (Lonchura striata domestica) songs contain a limited number of