The McCrae laboratory studies several projects relevant to vascular fuinction in health and disease. One involves the "antiphospholipid syndrome", a disorder characterized by of thrombosis and recurrent fetal loss in otherwise healthy individuals. Patients with this disorder have antibodies reactive with a plasma protein, beta2-glycoprotein 1, and we have shown that these antibodies activate endothelial cells in a beta2-GPI dependent manner. Activation is mediated through formation of a multiprotein complex on the endothelial surface that includes annexin A2 and TLR4, and we are characterizing this complex and the subsequent signaling pathway.
In a second project, we have studied the role of high molecular weight kininogen (HK) in regulating vascular function. We have prepared kininogen deficient mice, and found them to have enhanced angiogenesis and accelerated tumor growth. These mice are also protected from thrombosis and stroke yet do not have any predisposition to bleeding. We are currently developing strategies to deplete or inhibit kininogen in a therapeutic manner.
A third project focuses on the detection and function of microparticles in the development and propogation of vascular disease and cancer. Microparticles are subcellular particles derived from a number of cell types, that circulate in plasma. Microparticles promote thrombosis through expression of tissue factor, and carry mRNA and other genetic information that can be transferred among various cell types throughout the body. We will characterize the role of microparticles as an indicator of disease in humans, while further exploring their functions in vitro.
The McCrae laboratory studies several projects relevant to the function of blood vessels in health and disease. One project involves the "antiphospholipid syndrome", a disorder characterized by the development of blood clots in otherwise healthy individuals, as well as those with underlying autoimmune disease. We have shown that antibodies from these patients activate the endothelial cells lining blood vessels, making these vessels more likely to promote clotting. We are focused on better defining how this occurs, and developing novel means of preventing endothelial cell activation. In a second project, we study the role of microparticles, which are small pieces of cells that circulate in the blood, and promote blood clotting as well as transfer genetic information among cells throughout the body. The effects of microparticles are relevant both to thrombosis and tumor biology. In a third project, we have studied the role of kininogen in regulating a number of vascular functions. We have prepared genetically altered mice that lack kininogen, and found that they support increased growth of new blood vessels (angiogenesis) leading to more rapid tumor growth. The kininogen deficient mice are also protected from blood clots and stroke. We are working on strategies to deplete kininogen as a means of treating cardiovascular disease.
Merkoulov S, Zhang WM, Komar AA, Schmaier AH, Barnes E, Zhou Y, Luo G, Lu X, Iwaki T, Castellino FJ, McCrae KR. Deletion of murine kininogen gene 1 causes loss of plasma kininogen and delays thrombosis. Blood 111:1274-1281, 2008.
Ghosh A, Lei W, Febbraio M, Espinola RG, Cockrell E, McCrae KR, Silverstein RL. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in vivo. J Clin Invest 118:1934-1943, 2008.
Allen KL, Hamik A, Jain MK, McCrae KR. Endothelial activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors. Blood 117:6383-91, 2011.
Cheng V, Kashyap SR, Schauer PR, Kirwan JP, McCrae KR. Restoration of glycemic control in patients with type 2 diabetes mellitus after bariatric surgery is associated with reduction in microparticles. Surg Obes Related Dis (epub Oct, 2011).
Allen KL et al. A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2GPI antibodies. Blood 119:884-93, 2012.