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 cardiac death. 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.
Dilated cardiomyopathy (DCM), a complex cardiac disease characterized by an enlarged heart and poor cardiac functions is the most common cause for heart failure. The goal of this project is to study the underlying mechanisms of DCM by modeling endothelial dysfunction using patient-specific induced pluripotent stem cells. Results from this work could potentially lead to new strategies that could lower morbidity and mortality, but also improve the management of DCM patients.
|Paik, David T; Tian, Lei; Lee, Jaecheol et al. (2018) Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells. Circ Res 123:443-450|
|Stack, Jonathan P; Moslehi, Javid; Sayed, Nazish et al. (2018) Cancer therapy-induced cardiomyopathy: can human induced pluripotent stem cell modelling help prevent it? Eur Heart J :|
|Ma, Ning; Zhang, Joe Z; Itzhaki, Ilanit et al. (2018) Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation 138:2666-2681|
|Liu, Chun; Oikonomopoulos, Angelos; Sayed, Nazish et al. (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145:|
|Zhao, Ming-Tao; Chen, Haodong; Liu, Qing et al. (2017) Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs. Proc Natl Acad Sci U S A 114:E11111-E11120|
|Sayed, Nazish; Wu, Joseph C (2017) Towards Cardio-Precision medicine. Eur Heart J 38:1014-1016|
|Liu, Chun; Himmati, Farhan; Sayed, Nazish (2017) Paying the Toll in Nuclear Reprogramming. Front Cell Dev Biol 5:70|
|Sayed, Nazish; Ospino, Frank; Himmati, Farhan et al. (2017) Retinoic Acid Inducible Gene 1 Protein (RIG1)-Like Receptor Pathway Is Required for Efficient Nuclear Reprogramming. Stem Cells 35:1197-1207|
|Sharma, Arun; Burridge, Paul W; McKeithan, Wesley L et al. (2017) High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Sci Transl Med 9:|