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.

项目摘要/摘要：川崎病（Kawasaki disease， KD）是一种以儿童冠脉血管炎为主的疾病