The human heart is known to be a source of secreted signaling proteins, referred to as cardiokines. Evidence suggests that crosstalk signaling mediated by cardiokines may play key roles in fibrosis and other non-myocyte pathologies in patients with dilated cardiomyopathy (DCM), one of the most common forms of inherited heart disease. Beyond a few well-known examples, currently little is known about the identity of the proteins secreted by human heart cells and the signaling functions they carry. Research into the ?cardiac secretome? therefore has the potential to significantly advance our understanding of the roles of cardiac crosstalk in disease mechanisms. The Research Training Plan will leverage human induced pluripotent stem cell (iPSC), genome-editing, and proteomics technologies to examine cardiokine signals in normal and DCM iPSC-derived cardiac cells (Aim1) and their impact on crosstalk recipient cells (Aim 2).
In Aim 1, the applicant Dr. Edward Lau will train with mentor Dr. Joseph Wu in iPSC models and genome editing techniques in the K99 phase, investigate disease mechanisms through functional and transcriptomic analyses, then determine secreted cardiokines from normal vs. DCM iPSC-derived cardiomyocytes (iPSC-CM) using proteomics methods. The R00 phase will leverage the genome-edited iPSC models to investigate the secretory dynamics of major cardiac cell types and create a draft map of the human cardiac secretome in health and disease.
In Aim 2, Dr. Lau will train in iPSC-CM and iPSC-cardiac fibroblasts (iPSC-CF) co-culture models in the K99 phase, and complete a gene expression and functional study on the effect of co-cultured CM and CM-conditioned medium on iPSC-CF function. The R00 phase will further leverage this co-culture model to carefully examine the signaling impact of individual cardiokines including fibroblast growth factor 7 (FGF7) and FGF18 in cardiac crosstalk. Candidate Dr. Edward Lau has suitable prior training in cardiac proteomics and big data, with 32 publications including 10 as first-author since 2010. The Career Development Plan is tailored to enable Dr. Lau to gain new experimental skills and concepts in human iPSC biology and genome editing, as well as career skills through practice and coursework. Mentor Dr. Joseph Wu is a leading expert in stem cell biology and cardiovascular medicine. Co-mentor Dr. Jennifer Van Eyk (clinical proteomics) and advisors Dr. Euan Ashley (DCM) and Dr. Matt Porteus (genome-editing) offer complementary expertise. The Environment at Stanford Cardiovascular Institute directed by Dr. Wu is outstanding for collaborative and innovative research. Excellent infrastructure (iPSC biorepository, core facilities) is available. In summary, the strong mentoring environment and training plan are anticipated to fully prepare Dr. Lau to launch his independent career. The proposed studies promise to offer mechanistic insights into DCM pathogenesis, and may help identify therapeutic targets that can blockade disease crosstalk signaling in the heart.
Dilated cardiomyopathy (DCM) has an incidence of 1 in 2500 and is among the most prevalent inherited heart diseases worldwide. This study will investigate the molecular mechanisms of DCM by examining how proteins secreted from diseased cardiomyocytes can mediate crosstalk signaling to other cardiac cell types, in particular cardiac fibroblasts. Results obtained here may provide insights into the pathogenesis of DCM and promote the development of therapeutics to rescue inter-cellular disease signaling pathways.