Proteomic Investigations in Kawasaki Disease

描述（由申请人提供）：川崎病（KD）是一种影响婴儿和儿童的急性炎症性血管炎。如果不及时诊断和静脉注射免疫球蛋白（IVIG）治疗，KD可导致冠状动脉扩张或动脉瘤。KD的诊断是基于临床依据，没有专门的诊断测试。KD患儿被误诊而未得到治疗，不仅存在后遗症的风险，对于没有KD的患儿，也存在不必要的IVIG治疗相关的风险。因此，需要一种灵敏、特异的诊断试验。与KD相关的特征性全身体征提示血浆或尿液蛋白（生物标志物）的特定模式可能与该疾病相关。这些蛋白的鉴定可以更好地了解KD的病理生理，甚至为其病因提供线索。蛋白质模式也可以预测对IVIG治疗的反应性，可能有助于解释IVIG治疗的机制或预测冠状动脉扩张或动脉瘤的发展。本提案中正在测试的假设是：1)血浆或尿液中存在KD特有的蛋白质（生物标志物），可以将KD患儿与其他发热性疾病患儿区分出来，其中一些蛋白质至少部分与IG结合（特异性目标1）。2)IVIG影响KD患者血浆或尿液中这些游离肽或蛋白质生物标志物的数量（特异性目标2）。我们将开始验证这样的假设，即那些患有或发展为冠状动脉扩张或动脉瘤的KD患者在其血浆或尿液中具有独特的蛋白质模式，并且在诊断时的蛋白质模式可以识别那些疾病对IVIG有反应的儿童（特定目标3）。虽然超出了这一建议的范围，但我们进一步假设，其中一些蛋白质/肽参与了与KD相关的病理生理和症状，而IG缓解这些症状的机制是通过结合这些蛋白质/肽。这一建议的目标的成功完成将从回答这一重要的机械问题的基础上。该提案是为了响应NHLBI对“孤儿”心脏病进行新调查的请求。KD潜在的临床破坏性心脏后果和早期诊断在预防这些后果中的重要性鼓励我们开发和测试新的模式，以帮助诊断和潜在的预后这种相对罕见的疾病。

DESCRIPTION (provided by applicant): Kawasaki Disease (KD) is an acute inflammatory vasculitis that affects infants and children. If not diagnosed and treated promptly with intravenous immunoglobulin (IVIG), KD can result in coronary artery dilatation or aneurysms. The diagnosis of KD is made on clinical grounds and there is no specific diagnostic test. Not only is there risk of sequellae in children with KD who are misdiagnosed and not treated, there are also risks associated with unnecessary IVIG treatment in children who do not have KD. Therefore, there is a need for a sensitive and specific diagnostic test. The characteristic systemic signs associated with KD suggest that specific patterns of plasma or urine proteins (biomarkers) may be associated with the disease. Identification of these proteins may give better insight to the pathophysiology of KD, and even give clues to its etiology. Protein patterns may also be predictive of responsiveness to IVIG therapy, may help explain the mechanism of IVIG therapy or predict the development of coronary artery dilatation or aneurysms. The hypotheses being tested in this proposal are: 1) There are proteins in plasma or urine characteristic of KD (biomarkers) that can distinguish children with KD from those with other febrile illnesses, and that some of these proteins are at least partially bound to IG (Specific Aim 1). 2) IVIG affects the amount of these free peptide or protein biomarkers in the plasma or urine of patients with KD (Specific Aim 2). We will begin to test the hypotheses that those individuals with KD who have or develop coronary artery dilatation or aneurysms have a distinct protein pattern in their plasma or urine and that protein patterns at the time of diagnosis can identify those children whose disease will respond to IVIG (Specific Aim 3). Although beyond the scope of this proposal, we further hypothesize that some of these proteins/peptides are involved in the pathophysiology and symptoms associated with KD, and that the mechanism by which IG relieves these symptoms is by binding these proteins/peptides. The successful completion of the aims of this proposal will then from the basis for answering this important mechanistic question. This proposal is in response to an NHLBI request for novel investigations in "orphan" heart diseases. The potentially clinically devastating cardiac consequences of KD and the importance of early diagnosis in preventing them encouraged us to develop and test new modalities to aid in diagnosis, and potentially prognosis of this relatively rare disease.