Proteomic Investigations in Kawasaki Disease

描述(申请人提供)：川崎病(KD)是一种急性炎症性脉管炎，影响婴儿和儿童。如果不及时诊断和治疗静脉注射免疫球蛋白(IVIG)，KD可能导致冠状动脉扩张或动脉瘤。KD的诊断是以临床为基础的，没有特殊的诊断试验。不仅有被误诊和未治疗的KD儿童有后遗症的风险，而且对没有KD的儿童也有与不必要的IVIG治疗相关的风险。因此，有必要进行灵敏而特异的诊断试验。与KD相关的特征性全身症状表明，血浆或尿蛋白(生物标记物)的特定模式可能与疾病相关。对这些蛋白的鉴定可能会更好地了解KD的病理生理机制，甚至为其病因提供线索。蛋白质模式也可能预测IVIG治疗的反应性，可能有助于解释IVIG治疗的机制，或者预测冠状动脉扩张或动脉瘤的发展。1)血浆或尿液中具有KD(生物标志物)特征的蛋白质可以区分KD与其他发热性疾病的儿童，并且其中一些蛋白质至少部分地与IG结合(特异性靶标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)。我们将开始测试这样的假设，即那些患有或发展为冠状动脉扩张或动脉瘤的KD患者在他们的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其疾病对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KD相关的病理生理和症状，IG缓解这些症状的机制是通过结合这些蛋白质/肽来实现的。然后，这项提案的目标的圆满完成将为回答这一重要的机械问题奠定基础。这项建议是对NHLBI提出的对“孤儿”心脏病进行新研究的请求的回应。KD潜在的临床破坏性心脏后果以及早期诊断在预防它们方面的重要性鼓励我们开发和测试新的方法来帮助诊断和潜在地预测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.