"The ability to generate pluripotent stem cells (iPSC) by reprogramming somatic tissues is arguably the greatest breakthrough in biomedical science of the last decade. The most inaccessible cells of the body can now be derived repeatedly from any individual. This could have a huge impact on understanding disease and the development of new therapeutic drugs but it will require a new level of sophistication in bioassays to create disease models and monitor disease phenotypes. The project I propose here will take up this challenge for the cardiovascular system, creating new human models of heart failure and vascular disease that presently do not exist. My group is uniquely positioned in Europe to realize these ambitions through more than a decade of research on cardiac and vascular cells from human embryonic stem cells and more recently hiPSC; its present location in Leiden University Medical Centre is optimal for fostering clinical links. My group is one of few worldwide that uses conventional homologous recombination in human PSCs. My aims here are (1) develop protocols for differentiating all cells of the heart (2) engineer synthetic and native human myocardium that models healthy tissue and common disease states and (3) generate sets of isogenic diseased hPSC to model pathogenesis. This will be realized by deriving lineage marked “rainbow coloured” reporter hPSC lines, introducing selected (immature) cardiovascular cells into engineered constructs and subjecting them to mechanical/biochemical stress factors like cyclic contraction and fluid flow that would normally induce maturation and disease. The constructs will support simultaneous measurement of functional tissue parameters and include hiPSC from relevant diseases, genetically or pharmacologically rescued and isogenic hESC with the corresponding gene mutations. These new “sick human heart” and “ diseased vessel” models and novel bioassays will significantly advance technology to have major impact on the field."