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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：川崎病 (KD) 是一种主要表现为儿童的冠状血管炎，发达国家儿童获得性心脏病的最常见原因。尽管目前最好治疗后，大约四分之一的患者将持续发病。该提案提出了五项年研究职业发展计划，重点是川崎病炎症研究，目标是扩大对川崎病和心脏炎症的了解，并发展相关人员的技能和经验申请人。该研究建立在候选人最初的人类发现和随后的与以下相关的小鼠数据的基础上：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梗死，但其在炎症中的作用尚未得到很好的表征。初步数据表明 FSTL-1 与人类川崎病的炎症有关，以及在小鼠模型中，敲除蛋白质会加重疾病，而外源蛋白质治疗会减轻炎症。糖基化 FSTL-1可以下调巨噬细胞炎症反应，而巨噬细胞对于炎症反应至关重要 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 Th2 T 细胞表型并下调巨噬细胞炎症反应。该提案的目的是 1)：确定外源糖基化 FSTL-1 是否促进 Th2 T- 细胞表型并下调 KD 小鼠模型中的炎症巨噬细胞反应。 2）确定糖基化和非糖基化 FSTL-1 对人类巨噬细胞的影响是否存在差异体外炎症反应。 3) 定义KD中的炎症刺激是否诱导差异FSTL-1 使用人类诱导多能干细胞 (iPSC) 来研究心脏组织系中的亚型。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和心脏的新方法全身炎症。该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。这候选人有 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。当前的提案包括全面的指导和教学计划提高候选人发展免疫学专业知识所需的技能和分子生物学技能心脏炎症。在导师和顾问团队的指导下，他将提升自己的基础和转化研究技能。完成本培训计划将为候选人提供技能和成为一名成功的独立调查员的经验。