Vanderbilt University Medical Center has received a USD 1.77 million NIH R01 grant from the National Heart, Lung, and Blood Institute to investigate how mutations in the transcription factor TBX4 drive heritable pulmonary arterial hypertension, with a focus on identifying therapeutic targets in a disease that disproportionately affects children.
Heterozygous TBX4 variants represent the second most common genetic cause of heritable pulmonary arterial hypertension, a condition characterized by elevated pulmonary vascular resistance and, in TBX4-specific cases, concurrent alveolar hypoplasia. Despite its clinical significance, the downstream molecular mechanisms linking TBX4 loss to vascular pathology have remained poorly defined. The funded work, led by James D. West, centers on the role of pericytes — perivascular cells that regulate capillary stability and angiogenesis — as the primary effectors of TBX4-driven disease.
Preliminary data from the team's postnatal Tbx4 knockout mouse model indicate that loss of the transcription factor causes a phenotypic shift in pericytes away from an angiogenic state toward a vessel-stabilizing state, impairing pulmonary vascular development. The proposed mechanism involves derepression of RGS5, a direct TBX4 binding target, which suppresses PI3K signaling and underlies the pericyte phenotype switch. Human validation will use spatial transcriptomics in explanted lung tissue from TBX4-mutation patients and iPSC-derived pericyte models.
Current approved therapies for pulmonary arterial hypertension — including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin pathway agents — address hemodynamic consequences rather than genetic etiology. No TBX4-specific or pericyte-directed therapy exists. The PI3K-RGS5 axis identified here represents a potential precision target for a genetically defined patient subset, and the iPSC-based validation component adds direct translational relevance.