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

卵泡抑素样蛋白1在川崎病心脏炎症中的作用

• 批准号: 10091126
• 负责人: Mark Gorelik
• 金额: $ 16.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10091126
• 关键词: Acute; Acute Disease; Advisory Committees; Affect; Aftercare; Aneurysm; Anticoagulation; Attenuated; Basic Science; Biological Process; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Line; Cell Wall; Cells; Child; Childhood; Coculture Techniques; Color; Complement; Coronary; Cysteine; Data; Development; Diagnosis; Disease; Disease model; Dissection; Epithelial; Equipment; Event; Family; Family member; Fever; Fibroblasts; Flow Cytometry; Follistatin-Related Protein 1; Functional disorder; Funding; Glycoproteins; Goals; Heart; Heart Diseases; Human; Human Resources; Immune response; Immunohistochemistry; Immunology; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injections; Intention; Intervention; Investigation; Knock-out; Laboratories; Lactobacillus casei; Lesion; Life; Location; Mediator of activation protein; Mentors; Mentorship; Mesenchymal; Methods; Modeling; Molecular; Molecular Biology; Monitor; Morbidity - disease rate; Mucocutaneous Lymph Node Syndrome; Mus; Muscle Cells; Mutation; Myocardial Infarction; Myocardial rupture; Myocarditis; Parents; Pathogenesis; Patients; Phase; Phenotype; Plant Roots; Play; Post-Translational Protein Processing; Process; Production; Program Development; Protein Isoforms; Proteins; Recombinants; Research; Research Personnel; Risk; Role; Sampling; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Site; Spleen; Stenosis; Stimulus; Syndrome; T-Lymphocyte; Testing; Time; Tissues; Toddler; Training; Translating; Translational Research; Transplantation; Tunica Adventitia; Universities; Vasculitis; cardioprotection; career; career development; clinical application; coronary lesion; cytokine; experience; experimental study; glycosylation; heart function; immune function; in vivo; induced pluripotent stem cell; intima media; macrophage; medical schools; mortality; mouse model; novel; postnatal; professor; response; skills; systemic inflammatory response

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.

项目概要/摘要：川崎病（KD）是一种主要发生于儿童期的冠状动脉血管炎， 这是发达国家儿童获得性心脏病的最常见原因。尽管目前最好的 治疗后，大约四分之一的患者将有持续的发病率。该提案提出了一个五 一个为期一年的研究职业发展计划，重点是KD炎症的研究，目标是 扩大对KD和心脏炎症的理解，并发展其技能和经验， 申请人。这项研究建立在候选人最初的人类发现和随后的小鼠数据的基础上， 一种重要的心脏相关蛋白，称为卵泡抑素样蛋白1（FSTL-1）在KD中的作用。FSTL-1具有 已被证明在心肌损伤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。 梗死，但其在炎症中的作用尚未得到很好的表征。初步数据显示，FSTL-1是 与人类川崎中炎症相关，以及在小鼠模型中， 蛋白质可减轻疾病，而用外源蛋白质治疗可减轻炎症。糖化 FSTL-1可以下调巨噬细胞的炎症反应，而巨噬细胞对于FSTL-1的表达是至关重要的。 KD的发展。候选人将研究FSTL-1在心脏炎症中的作用，假设 FSTL-1的糖基化形式是心脏炎症的反调节剂，促进Th 2 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Th 2 T- 细胞表型，并下调KD小鼠模型中的炎症巨噬细胞反应。（二） 确定糖基化和非糖基化FSTL-1是否差异性地影响人巨噬细胞 体外炎症反应。3)确定KD中的炎症刺激是否诱导差异FSTL-1 在心脏组织系中的同种型，使用人诱导多能干细胞（iPSC）。 这些目标的实现将阐明FSTL-1（心脏功能的关键介质）的作用。 在心脏炎症的情况下，并允许研究调节心脏炎症的新方法， 全身炎症。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转化研究。的 候选人有75%的保护时间用于研究，实验室和办公空间，以及供应资金， 设备和人员的费用。目前的建议包括一个全面的指导和教学计划， 提高候选人的技能和发展免疫学专业知识所需的分子生物学， 心脏炎症在他的导师和顾问团队的指导下，他将推进他的基本和 翻译研究技能。完成本培训计划将为候选人提供技能， 成为成功的独立调查员。