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.
Kawasaki disease is the number one cause of acquired heart disease in childhood in the developed world. Study of the role of FSTL-1 will advance the study of this disease by establishing how this critical mediator of cardiac function modulates inflammation and immune function. Lessons from these findings can be applied in a directly translational manner, including trials of use of recombinant FSTL-1 for treatment of cardiac inflammation in Kawasaki disease.
