Project 1. Mechanisms of antigen-antibody recognition in Antiphospholipid Syndrome

Antiphospholipid antibodies (aPLs) cause thrombosis and pregnancy morbidly in patients with the autoimmune disorder Antiphospholipid Syndrome (APS).  However, the underlying mechanisms of aPLs-induced thrombosis and aPL-induced obstetric complications are not understood.  This gap in knowledge complicates the development of new diagnostic tests enabling the identification of patients at higher risk of developing blood clots in veins, arteries, and placenta.  It also impairs the development of APS-specific therapeutics, which currently do not exist.  To fill this gap in knowledge, we study how aPLs interact with protein antigens at the molecular level and how immunogenic complexes crosstalk with the complement and coagulation cascades.  Our laboratory primarily focuses on autoantibodies targeting the plasma proteins beta-2 glycoprotein I and prothrombin, which are the most common aPL found in thrombotic APS patients.  This project is in part funded by the grant number by the NHLBI (grant number HL150146). 

Project 2. Structural enzymology of protein disulfide isomerase in thrombosis

Protein disulfide isomerases constitute a large family of enzymes essential for life.  Intracellularly, they are responsible for oxidative protein folding.  Extracellularly,  they play important regulatory roles, most notably in thrombus formation.  They can also participate in immunological responses by supporting antigen presentation and modulating the function of plasma proteins recognized by antiphospholipid antibodies, like we recently found for beta-2 glycoprotein I.  Our laboratory explores the structure, function, and allosteric regulation of the longest known and arguably the most important member of the family, that is, protein disulfide isomerase (PDI).  Our goal is to identify critical regulatory pathways of extracellular PDI that can be exploited pharmacologically to modulate their oxidoreductase and chaperone activities.