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VascularGrowth Report Summary

Project ID: 307460
Funded under: FP7-IDEAS-ERC
Country: Turkey

Mid-Term Report Summary - VASCULARGROWTH (Bioengineering prediction of three-dimensional vascular growth and remodeling in embryonic great-vessel development)

Globally 1 in 100 children are born with significant congenital heart defect, representing either new genetic mutations or epigenetic insults that alter cardiac morphogenesis in utero. One major epigenetic insult is abnormal tissue stresses that may develop due to blood flow and pressure. Particularly embryonic CV systems dynamically regulate structure and function over very short time periods throughout morphogenesis and that biomechanical loading conditions within the heart and great-vessels alter morphogenesis and gene expression. During the first two quarters of the ERC Starting Grant project, my laboratory has pioneered and established itself in embryonic cardiovascular biomechanics and published over 20 peer-reviewed manuscripts. After setting up our research lab and training core research team we demonstrated and validated a practical animal model of a clinically relevant congenital heart disease that will allow us to study the prognosis of embryonic arterial diseases and explore fetal engineering interventions intended to cure these diseases. Our team focused on early embryonic aortic arch development, which is central to several major congenital heart defects. Specific accomplishments include the completion of time-resolved, three-dimensional and multi-modal anatomy, microstructural, genetic, pressure and flow data for a critical period during normal embryonic arch development. The acquisition real-time PCR data on a large set of mechanosensitive genes fom normal developing aortic arch segments, as well as their controls are completed. We have finalized the theoretical foundation of our proposed optimization growth models, expanded them to three-dimensions and addressed a key challenge on size, material and hemodynamic scaling. We have configured advance microscopy systems to image time-lapsed changes of vascular microstructure and hemodynamic loading so that we can validate these computational models or aortic arch development. Early embryonic vascular experiments are performed on live vessels having 40-80μm diameters are very challenging. For example, we have successfully designed novel micro-pressure systems to conduct mechanical tests on micron size arteries. These mechanical measurements are integrated with our recently established time-lapsed 3D optical coherence tomography imaging expertise resulting simultaneous mechanical and biological data from developing embryonic systems. Lastly, we have established methods to quantify the key structural proteins that exist in embryonic arch vessels and performing detailed immunohistochemistry experiments. Project team has just finished work packages related to the normal development. During the second half of the project, as planned in the original proposal we will focus on abnormal development and applying the diseased models that have been developed during the first half of the project. These activities are now evolving towards gene-pathway network analysis and integrating this bioinformatics knowledge with soft tissue mechanics growth models. Multidisciplinary application of bioengineering principles to CHD is likely to provide novel insights and paradigms towards our long-term goal of optimizing CHD interventions, outcomes, and the potential for preventive strategies.

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