Matrix Metalloproteinases in Kawasaki Disease

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DESCRIPTION (provided by applicant): Kawasaki disease (KD) is the most common cause of acquired cardiovascular disease in childhood in the United States. KD presents a unique dilemma for the clinician: the disease may be difficult to recognize, there is no diagnostic laboratory test, there is an extremely effective therapy, and there is a 25% chance of serious cardiovascular damage or death if the therapy is not administered. Matrix metalloproteinases (MMPs) are secreted by cells in the vascular wall and degrade components of the extracellular matrix (ECM). MMPs have been implicated in atherosclerosis, plaque rupture, and aneurysm formation and polymorphisms in these genes have been associated with susceptibility to atherosclerosis and aneurysm formation. The short-term goals of the PI are to study children with KD as a unique population in which to explore the role of MMPs in vascular damage and the association of MMP polymorphisms with aneurysm formation. The following hypotheses will be tested: 1) MMPs play a key role in injury and remodeling of the vessel wall in children with KD, 2) Pattems of MMP activation and detection of ECM degradation products may be used as a diagnostic test for KD, and 3) Polymorphic MMP alleles are associated with increased susceptibility to KD and with aneurysm formation. This work will lead to new insights into the role of MMPs in KD and general mechanisms of aneurysm formation. Data from this project will be used to determine if there is a role for MMP inhibitors in the treatment of children with KD. The long-term goals of the PI are to understand the pathogenesis and etiology of KD, which will lead to more specific treatment strategies and disease prevention. The PI will mentor two new fellows in clinical research projects related to treatment of IVIG non-responders and non-invasive studies of endothelial cell function. Other trainees (graduate and medical students) will be involved in KD-related clinical projects. The PI will mentor two new UCSD medical students each summer on the NIH Student Research training grant at UCSD. This K24 award will allow the PI to relinquish administrative responsibilities and to share clinical responsibilities with the fellows to allow more time for mentoring activities.