PI Joseph Ahearn
Co-Investigator William Wagner
Title Molecular and Functional Characterization of the Lupus Platelet
Description The platelet plays critical roles in control of abnormal bleeding, in formation of pathologic thromboses, and in molecular and cellular mechanisms of inflammation, wound healing, and the immune response. Recently it has been found that platelets can also participate in atherothrombosis and inflammation through the formation and release of membrane-bound vesicles called microparticles. These platelet-derived microparticles (PMP) readily circulate in the vasculature and exhibit procoagulant activity. Platelets and PMP are likely to contribute to myriad manifestations of lupus, although they appear to be relatively understudied in this regard. We have recently discovered that platelets bearing complement activation product C4d (PC4d) are highly specific for lupus versus other inflammatory diseases (98%) and versus healthy subjects (100%). PC4d-positivity in patients with lupus is associated with neuropsychiatric and thrombotic manifestations of the disease. Through imaging and flow cytometric studies we have since discovered that PC4d associates not only with intact platelets, but also with membrane-bound PMP. This study has two central hypotheses: first, that C4d deposition on platelets and PMP has functional consequences that contribute to thrombotic manifestations in lupus, and second, that platelets bearing C4d hold molecular clues to a pathway responsible for the PC4d phenotype and to pathways that lead to the functional consequences of PC4d deposition. This application will specifically focus on determining differences, both functional and molecular, between PC4d-positive and PC4d-negative platelets in patients with SLE. This will be accomplished through three specific aims. The first aim is to investigate functional differences between PC4d-positive and PC4d-negative platelets with regard to thrombogenesis and atherogenesis. The second aim is to investigate the functional effect of PC4d-positive versus PC4d-negative PMP on immune cells and other cellular components of the vasculature. The third aim is to identify specific protein differences in C4d-positive platelets compared to C4d-negative platelets in patients with SLE and in healthy controls. Successful completion of the proposed studies should advance our understanding of the functional role of platelets, PMP, and complement in the thrombotic manifestations of lupus. In addition, identification of a lupus platelet proteomic signature would elucidate important molecular and cellular mechanisms of thrombotic and other complications of lupus and would identify potential therapeutic targets.
Source Department of Defense
Term 7/1/09 – 6/30/12