The Role of Follistatin Like Protein 1 in the cardiac inflammation of Kawasaki Disease

项目摘要/摘要：川崎病(KD)是一种以儿童冠状血管炎为主的疾病， 这是发达国家儿童获得性心脏病最常见的原因。尽管目前是最好的 如果接受治疗，大约四分之一的患者会有持续性的发病率。这项提案提出了五项建议 一年的研究职业发展计划，重点是KD的炎症研究，目标是 扩大对KD和心脏炎症的认识，发展治疗的技能和经验 申请人。这项研究建立在候选人最初的人类发现和随后的老鼠数据的基础上，这些数据与 一种重要的心脏相关蛋白--卵泡抑素样蛋白1(FSTL-1)在KD中的作用。FSTL-1具有 已被证明在心肌梗死后保护心肌细胞和成纤维细胞方面具有明确和关键的作用 心肌梗死，但其在炎症中的作用尚未得到很好的描述。初步数据显示，FSTL-1是 与人类川崎病的炎症有关，在小鼠模型中，敲除 蛋白质加重疾病，而外源蛋白质治疗则减轻炎症。糖基化 FSTL-1可以下调巨噬细胞的炎症反应，而巨噬细胞在 KD的发展。候选人将研究FSTL-1在心脏炎症中的作用，假设 糖基化形式的FSTL-1是心脏炎症的反向调节因子，促进Th2 T细胞 表型和下调巨噬细胞炎症反应。 该提案的目的是：1)确定外源性糖基化FSTL-1是否促进Th2 T- 在KD小鼠模型中，细胞表型和下调炎性巨噬细胞反应。2) 确定糖基化和非糖基化FSTL-1是否对人巨噬细胞有不同的影响 体外炎症反应。3)明确KD患者炎性刺激是否诱导FSTL-1的差异 使用人类诱导多能干细胞(IPSC)的心脏组织系中的异构体。 这些目标的实现将阐明FSTL-1(心脏功能的关键介质)的作用。 在心脏炎症的背景下，并允许研究调节心脏和 全身炎症。这位候选人是哥伦比亚大学医学院的助理教授 并坚定地致力于炎症和免疫学的基础和翻译研究。这个 候选人有75%的受保护时间用于研究、实验室和办公空间，以及用品资金， 设备和人员。目前的提案包括一项全面的指导和说教计划，以 提高候选人的技能和在分子生物学方面的技能，以发展免疫学和 心脏发炎。在他的导师和顾问团队的指导下，他将推进他的基础和 翻译研究技能。完成此培训计划将为应聘者提供技能和 成为一名成功的独立调查员的经验。

Project Summary/Abstract: Kawasaki disease (KD), a predominantly coronary vasculitis of childhood, is the most common cause of acquired heart disease of childhood in the developed world. Despite current best treatments, approximately one quarter of patients will have persistent morbidity. This proposal presents a five year research career development program with a focus on the study of inflammation in KD, with the goals of expanding understanding of KD and cardiac inflammation, and developing of skills and experience of the applicant. The study builds on the candidate's initial human finding and subsequent murine data relating to the role of an important cardiac-related protein known as Follistatin-Like Protein 1 (FSTL-1) in KD. FSTL-1 has been shown to have defined and critical roles in protecting cardiac myocytes and fibroblasts after myocardial infarct, but its role in inflammation has not been well characterized. Preliminary data shows that FSTL-1 is associated with inflammation in Kawasaki disease in humans, and that in a mouse model, knockout of the protein aggravates disease while treatment with exogenous protein attenuates inflammation. Glycosylated FSTL-1 can downregulate macrophage inflammatory responses, and macrophages are critical for the development of KD. The candidate will study the role of FSTL-1 in cardiac inflammation, hypothesizing that the glycosylated form of FSTL-1 is a counter-regulator of cardiac inflammation, promoting a Th2 T-cell phenotype and down-regulating the macrophage inflammatory response. The aims of the proposal are 1): Determine whether exogenous glycosylated FSTL-1 promotes a Th2 T- cell phenotype and downregulates the inflammatory macrophage response in the mouse model of KD. 2) Establish whether glycosylated and non-glycosylated FSTL-1 differentially affect the human macrophage inflammatory response in vitro. 3) Define whether inflammatory stimulus in KD induces differential FSTL-1 isoforms in cardiac tissue lines, using human induced pluripotent stem cells (iPSC). The accomplishment of these aims would clarify the role of FSTL-1 (a critical mediator of cardiac function) in the setting of cardiac inflammation and allow investigation into novel methods of modulating cardiac and systemic inflammation. The candidate is an assistant professor at the Columbia University School of Medicine and is firmly committed to a career in basic and translational research in inflammation and immunology. The candidate has 75% protected time for research, laboratory and office space, and funding for supplies, equipment and personnel. The current proposal includes a comprehensive mentorship and didactic plan to advance the candidate's skills and in molecular biology required for developing expertise in immunology and cardiac inflammation. Under the guidance of his mentor and advisory team, he will advance his basic and translational research skills. Completion of this training plan will provide the candidate with the skills and experience to become a successful independent investigator.