Matrix Metalloproteinases in Kawasaki Disease

描述（由申请人提供）： 在美国，川崎（KD）是儿童期获得性心血管疾病的最常见原因。KD给临床医生带来了一个独特的困境：这种疾病可能很难识别，没有诊断性实验室检查，有一种非常有效的治疗方法，如果不进行治疗，有25%的机会发生严重的心血管损伤或死亡。基质金属蛋白酶（MMP）由血管壁中的细胞分泌并降解细胞外基质（ECM）的组分。基质金属蛋白酶与动脉粥样硬化、斑块破裂和动脉瘤形成有关，这些基因的多态性与动脉粥样硬化和动脉瘤形成的易感性有关。PI的短期目标是将KD儿童作为一个独特的人群进行研究，探讨MMP在血管损伤中的作用以及MMP多态性与动脉瘤形成的相关性。将检验以下假设：1）MMP在KD儿童血管壁损伤和重塑中起关键作用，2）MMP活化模式和ECM降解产物检测可用作KD的诊断试验，3）多态性MMP等位基因与KD易感性增加和动脉瘤形成相关。这项工作将导致对基质金属蛋白酶在KD中的作用和动脉瘤形成的一般机制的新见解。该项目的数据将用于确定MMP抑制剂是否在治疗KD儿童中发挥作用。PI的长期目标是了解KD的发病机制和病因，这将导致更具体的治疗策略和疾病预防。PI将指导两名新研究员参与与IVIG无应答者治疗和内皮细胞功能非侵入性研究相关的临床研究项目。其他学员（研究生和医学生）将参与KD相关的临床项目。PI将指导两个新的UCSD医学生每年夏天在UCSD的NIH学生研究培训补助金。这个K24奖项将允许PI放弃行政责任，并与研究员分享临床责任，以便有更多的时间进行指导活动。

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.