Proteomic Investigations in Kawasaki Disease

描述（由申请方提供）：川崎病（KD）是一种影响婴儿和儿童的急性炎症性血管炎。如果没有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的诊断是基于临床基础，没有特定的诊断测试。KD患儿不仅存在误诊和未治疗的后遗症风险，而且还存在与未患KD的儿童不必要的IVIG治疗相关的风险。因此，需要一种灵敏且特异的诊断测试。与KD相关的特征性全身体征表明，血浆或尿蛋白（生物标志物）的特定模式可能与疾病相关。这些蛋白质的鉴定可以更好地了解KD的病理生理学，甚至提供其病因学的线索。蛋白质模式也可以预测对IVIG治疗的反应性，可以帮助解释IVIG治疗的机制或预测冠状动脉扩张或动脉瘤的发展。本提案中正在检验的假设是：1）血浆或尿液中存在KD特征性蛋白（生物标志物），可以将KD儿童与其他发热性疾病儿童区分开来，并且其中一些蛋白至少部分与IG（特异性目的1）结合。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量（特异性目的2）。我们将开始检验以下假设：患有或发展为冠状动脉扩张或动脉瘤的KD个体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其疾病将对IVIG有反应的儿童（特定目标3）。尽管超出了本建议的范围，但我们进一步假设这些蛋白质/肽中的一些参与了与KD相关的病理生理学和症状，并且IG缓解这些症状的机制是通过结合这些蛋白质/肽。成功地完成这一建议的目标将为回答这一重要的机械问题奠定基础。该提案是对NHLBI要求对“孤儿”心脏病进行新研究的回应。KD潜在的临床破坏性心脏后果以及早期诊断在预防中的重要性鼓励我们开发和测试新的模式来帮助诊断，以及这种相对罕见的疾病的潜在预后。

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.