Antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by thrombosis and/or recurrent fetal loss. Beta2-glycoprotein I (?2GPI) is the major antigen for the antibodies associated with APS. Only the dimeric form of 2GPI generated by anti-2GPI antibodies is pathologically important, in contrast to monomeric 2GPI which is abundant in plasma. The primary hypothesis of the proposed study is that the interaction of 2GPI/anti-2GPI antibody complexes with lipoprotein receptors and anionic phospholipid is a potential drug target for interfering with thrombosis in APS. We created a dimeric inhibitor to selectively target dimeric 2GPI in 2GPI/anti-2GPI antibody complexes. This inhibitor disrupts the binding of 2GPI/antibody complexes with lipoprotein receptors and anionic phospholipid. The proposed studies will optimize the inhibitor that blocks the interaction of 2GPI/anti-2GPI antibody complexes with lipoprotein receptors and anionic phospholipid;use the inhibitor, site-directed mutagenesis, and functional studies in cells and in vivo to dissect the contribution of lipoprotein receptors and anionic phospholipid to thrombosis in APS. The studies will employ biophysical measurements of domain interactions, NMR and crystallographic determination of protein structures, cell-based assays and laser-induced thrombosis in live mice in pursuit of these goals.

Public Health Relevance

Beta2-glycoprotein I ( 2GPI) is the major antigen for the antibodies associated with antiphospholipid syndrome (APS); an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. APS patients with thrombosis are treated chronically with general antithrombotic medications which are not always effective. We will use in vivo mouse model in combination with biochemical and biophysical studies to understand how 2GPI/anti-2GPI antibody complexes interact with cellular receptors leading to thrombosis in APS. The insights gained from the study could be used as a basis for new treatments for people suffering from APS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096693-04
Application #
8623142
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Kindzelski, Andrei L
Project Start
2011-04-07
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$426,300
Indirect Cost
$181,300
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Kolyada, A; Ke, Q; Karageorgos, I et al. (2016) Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome. J Thromb Haemost 14:1298-307
Kolyada, Alexey; Karageorgos, Ioannis; Mahlawat, Pardeep et al. (2015) An A1-A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome. FEBS J 282:864-73
McMillan, Brian J; Schnute, Björn; Ohlenhard, Nadja et al. (2015) A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. Mol Cell 57:912-24
Mottarella, Scott E; Beglov, Dmitri; Beglova, Natalia et al. (2014) Docking server for the identification of heparin binding sites on proteins. J Chem Inf Model 54:2068-78
Kolyada, Alexey; Porter, Andrew; Beglova, Natalia (2014) Inhibition of thrombotic properties of persistent autoimmune anti-*2GPI antibodies in the mouse model of antiphospholipid syndrome. Blood 123:1090-7
Kolyada, Alexey; De Biasio, Alfredo; Beglova, Natalia (2013) Identification of the binding site for fondaparinux on Beta2-glycoprotein I. Biochim Biophys Acta 1834:2080-8
Kolyada, Alexey; Lee, Chang-Jin; De Biasio, Alfredo et al. (2010) A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/antibody complexes implicated in antiphospholipid syndrome. PLoS One 5:e15345