Dilated cardiomyopathy (DCM) is a type of heart disease characterized by poor pumping function. DCM is the
most common cause of heart failure and is also the leading reason for heart transplantation. Major gaps exist
in our understanding of the pathophysiology of DCM and the disease may be mild to severe. Despite
aggressive regimen for DCM treatment, most of the patients die due to progressive heart failure or sudden
To date, mutations in more than 60 genes have been implicated to cause familial DCM, including genes that
encode sarcomeric, cytoskeletal, nuclear and plasma membrane proteins. Mutations in the gene that encodes
the nuclear envelope proteins lamin A and C (LMNA) are now considered to be the most common cause of
DCM. However, the molecular mechanisms that underlie “cardiolaminopathy” remain elusive, and it is unknown
why mutations in this ubiquitously expressed gene have such a disproportionate effect on the heart. In addition
to having its effect on the heart, LMNA mutations have also been implicated in endothelial (EC) dysfunction.
As EC dysfunction has been known to contribute to DCM, I hypothesize that EC dysfunction due to LMNA
mutation has a significant impact on the pathogenesis and disease progression of DCM. Moreover,
understanding the underlying mechanisms of EC dysfunction in DCM patients could help in the better
management of the patients. Using induced pluripotent stem cells (iPSC) technology, I propose to model EC
dysfunction in LMNA-related DCM patients. For this: (1) I will generate and characterize patient-specific iPSC-
ECs from LMNA-mutated DCM patients and family controls; (2) conduct detailed molecular and functional
analyses of these iPSC-ECs to delineate the mechanisms responsible for EC dysfunction; and (3) harness the
potential of genome-editing technology to recapitulate the disease phenotype.
I have significant track record of research in vascular and EC biology, stem cell biology, and cardiovascular
diseases, and by using this grant opportunity I will further expand my technical skills and career development
activities by closely interacting with my faculty mentor, advisory committee, and collaborators in these areas. At
the end of the K01 award, I intend to compete for an academic position and obtain R01 funding. Together, with
full institutional support in a rich institutional environment, my mentor and advisory committee are fully
committed to facilitate my successful transition to an independent investigator.