Marlene Rabinovitch, M.D., Mark Nicolls, M.D., and Roham Zamanian, M.D.

Project 1: Dysregulated Immune Responses and PAH

  • Relate altered B cell activation and immunity to the development of PAH and neointimal lesions in a mouse model for PAH. We employ transgenic mice where PAH is induced by infection with MHV-68. For this project, we will study four transgenic mouse lines: BMPR2 ±, S100A4 over-expressing, miR 155-/- and IFNγR-/-.
  • Relate the B cell activation abnormalities observed in the mice to those in patients with Idiopathic PAH, Connective Tissue Disease APAH and other forms of APAH. Investigating the role of Complement activation and immune complex formation in the pathogenesis Idiopathic PAH, Connective Tissue Disease APAH and other forms of APAH.
  • Identification of specific antigens targeted by autoantibodies in immune complexes deposited in the lung and pulmonary arterial wall in idiopathic PAH, Connective Tissue Disease APAH and other forms of APAH.
  • Development and characterization of a new rat model of autoimmune pulmonary hypertension.
  • Use of mass spectrometry platforms for analyzing lipid inflammatory mediators implicated in pathogenesis of pulmonary vascular disease.
  • Development of bone morphogenetic protein receptor-2 (BMPR2) transgenic rats to genetically model human pulmonary hypertensive conditions.
  • Elucidation of inflammation profiles in systemic sclerosis pulmonary arterial hypertension patients through multiplex cytokine assays.

Related Projects in the Rabinovitch Lab, funded by the NIH/NHLBI (R01, R03, P01, U01 grants)

  • The use of genetically modified mice to study novel genes implicated in pulmonary vascular pathobiology.
  • The pivotal role of PPARgamma in the BMP signaling pathway in maintaining endothelial function and vascular regeneration and in preventing vascular pathology
    Dysregulation of Elastin Production and Assembly in Pulmonary Hypertension and Other Vascular Pathologies.
  • High-throughput Screen of FDA-Approved Drugs or micro RNA Aptomers for Candidates that Increase BMPR2 Signaling, and Can be Used to Prevent or Reverse Pulmonary Hypertension.
  • The use of induced pluripotent stem cells transdifferentiated into vascular cells and next generation sequencing (whole genome sequencing, Methyl-Seq, RNA-Seq) to identify novel pathways in pulmonary hypertension and personalized approached to treatment.
  • The translation of elafin from its role as an endogenous elastase inhibitor to a therapy for pulmonary hypertension. Additional mechanisms of action related to proteosome inhibition and anti-inflammatory, and pro-angiogenic properties.