University of California, San Francisco has received a USD 1.63 million NIH R01 grant from the National Heart, Lung, and Blood Institute to investigate the molecular mechanisms driving pulmonary veno-occlusive disease (PVOD), a rare and frequently misdiagnosed subtype of pulmonary hypertension for which no approved drug therapies exist. The award, running through February 2030, funds work led by investigator Akiko Hata in UCSF's biochemistry department.
PVOD is clinically and radiographically indistinguishable from pulmonary arterial hypertension (PAH), yet applying standard PAH vasodilator therapies to PVOD patients can precipitate life-threatening pulmonary edema. That diagnostic ambiguity drives significant misclassification and patient harm, making the identification of PVOD-specific biomarkers and therapeutic targets a pressing unmet need.
The Hata lab's approach centers on two intersecting mechanisms. The first involves a circulating complex formed by Rad51, a DNA double-strand break repair enzyme, and VE-cadherin (cadherin 5), an endothelial adherens junction protein. Preliminary data indicate that exposure to mitomycin C — a chemotherapeutic agent known to induce PVOD in cancer patients — causes this Rad51/VE-cadherin complex (VRC) to be shed into circulation, increasing vascular permeability and compromising endothelial barrier integrity. The team proposes evaluating circulating VRC as a blood-based diagnostic biomarker capable of distinguishing PVOD from PAH.
The second mechanism involves the integrated stress response (ISR). Hereditary PVOD is associated with biallelic loss-of-function mutations in EIF2AK4, encoding the kinase GCN2, which phosphorylates eIF2α to suppress global protein synthesis and activate the ISR. Mitomycin C treatment also depletes GCN2, effectively recapitulating the genetic lesion. The grant will examine how maladaptive ISR activation following GCN2 loss contributes to venular and capillary remodeling — the pathological hallmark that distinguishes PVOD from arterial-predominant PAH.