Smyth Lab

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inflam

Inflammation and Thrombosis Program 

 Drawing on a long-standing interest in platelet biology, our groups has established animal models for studying the role of platelet membrane proteins in thrombosis and the response to arterial injury, and has delineated specific signaling systems responsible for mediating platelet-leukocyte interactions and for inflammation in the context of arterial injury and cardiac hypertrophy.  Smyth’s interest in understanding the functional interplay between thrombosis and inflammation has resulted in observations about beneficial effects of antiplatelet drugs in infectious and inflammatory states of pneumonia and sepsis. This work has also spawned clinical trials of the effects of antithrombotic therapy on inflammation and the identification of biomarkers of ischemic heart disease. Her research group continues to identify novel signaling pathways in platelets, which likely will be the target for future translational studies.  [Back to Top]

Lysolipid Signaling Program

Our group also has a longstanding research interest in the role of bioactive lysophospholipid, such as lysophosphatidic acid (LPA), as mediators of cardiovascular disease. The lysophospholipase D autotaxin (ATX) catalyzes the hydrolysis of circulating or cell-associated lysophosphatidylcholine (LPC) to generate LPA, which has potent, receptor-mediated effects on blood and vascular cells.  LPA is a proteotypic member of a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, apoptosis and development.  Our contributions to the literature include characterizing pathways for production and metabolism of LPA in the circulation; providing the first evidence of a pathologic role for LPA receptors in the response to arterial injury; identifying key structural and functional elements of ATX and mechanisms for regulation of ATX function by localization along cell surfaces.  Current work is focused on identifying mechanistic links between dietary intake of lipids and cardiovascular disease risk. Current investigations are exploring the possibility that choline-containing lipids and adipose-derived ATX serve as links between diet and cardiovascular disease risk.

LPA can hydrolyzed and inactivated by lipid phosphate phosphatase (LPP) enzymes present on cell membranes.  A genome-wide association studies (GWAS) identified the PLPP3/PPAP2B gene encoding LPP3 as a novel loci associated with coronary artery disease susceptibility.  We have established that LPP3 expression in mice is critical to attenuate inflammation, reduce smooth muscle cell proliferation, and maintain endothelial barrier function following vascular injury in an LPA-dependent manner. Current studies are focused on understanding how heritable human variation in PLPP3/PPAP2B predisposes to the development and/or complications of atherosclerosis, which may ultimately translate into the validation of novel pathways for disease prevention. 

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