Familial dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy (HOM) are considered the two most common causes of inherited cardiovascular diseases. Previously, it has been difficult to study these diseases in human models because of limited access to human cardiomyocytes and difficulty growing them. With the discovery of human induced pluripotent stem cells (iPSCs) and the increased efficiency and reproducibility of differentiating them into beating cardiomyocytes (iPSC-CMs), the landscape has dramatically changed. For the first time, it is now possible to create patient-specific and disease-specific cell lines to improve our understanding of the molecular mechanisms of DCM and HCM. Hence the major goals of this multidisciplinary R24 Resource-Related Research Project are (i) generation, (ii) characterization, (iii) sequencing, and (iv) distribution of cardiac iPSC lines. Over the next 5 years, we plan to create an iPSC bank of 600 lines derived from control individuals, HCM patients, and DCM patients. To accomplish these goals, we have assembled a truly collaborative team of investigators with expertise in cardiovascular medicine, iPSC biology, developmental biology, next generation sequencing (NGS) technology, population genetics, biomedical informatics, large-scale database repository, and business development. We propose the following 4 Specific Aims over the next 5 years:
Aim 1 : To generate 600 iPSC lines from controls, DCM, and HCM patients.
Aim 2 : To evaluate drug safety screening using iPSCs (clinical trial in a petri dish).
Aim 3 : To obtain genotype-phenotype information using DNA-seq and RNA-seq.
Aim 4 : To distribute IPSC lines and their genotype-phenotype data to academic community. In summary, we believe this R24 will address a national need and fulfill NHLBI's strategic vision of creating a novel biorepository (iPSC-genotype-phenotype) that is valuable to the broader scientific community. Given our expertise and track record, we are confident we can deliver on these milestones.
Cardiovascular disease is the number one cause of morbidity and mortality in the US. The advent of IPSC technology now allows us to (i) study disease mechanism, (ii) perform drug screening, and (iii) link with genotype/phenotype data. This R24 will create a unique resource of 600 IPSC lines that will promote collaboration among academia, industry, and government and accelerate discovery in translational medicine
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