Our long-term objective is to determine the influence biophysical forces have on heart development and how alterations of these forces early in development can lead to congenital heart defects (CHDs). CHDs are extremely prevalent affecting almost 36,000 newborns in the US each year, or 9 out of 1,000 live births. In order to tease apart what molecular pathways are being regulated by biomechanics, we will be developing new technology (optical pacing) capable of perturbing cardiac dynamics in precise ways. Previous perturbation techniques have involved gross manipulations (vessel ligation, conotruncal banding, etc.) that do not offer the necessary control to determine the exact influences of biomechanics on development. We have demonstrated that optical pacing is capable of consistently pacing early embryonic quail hearts in vivo in a precise manner over a range of developmental stages without causing damage to the tissue. Recent data shows that we can modify the level of regurgitant flow in the outflow tract thereby altering oscillatory shear stress (OSS). It has been suggested that shear forces in the outflow tract are needed for normal development of valves and septa. Outflow tract defects which make up 15-20% of CHDs are very serious requiring surgical intervention. As a demonstration of the potential of OP, we will create a model of abnormal regurgitant flow in the outflow tract and investigate the impact of this change in shear force on molecular expression and morphogenesis during cardiac development. Experiments will be conducted to determine the optimal energy requirements for optical pacing and these optimal settings will be utilized to develop optical pacing protocols that consistently change the levels OSS in the outflow tract to precise degrees. Optical coherence tomography will be employed to refine optical pacing methods and to measure hemodynamics and morphology both during and after optical pacing. Upon completion, we will have optimized and characterized OP as a new experimental tool, used that tool to create a model of abnormal regurgitant flow in the outflow tract, and investigated the impact of this change in shear force on gene expression and morphogenesis during cardiac development. This experimental tool will be valuable more broadly for uncovering the mechanisms of mechanically transduced signaling in the early developing heart, which will enable us to develop a better understanding of the etiology of congenital defects. OP has the potential to manipulate cardiac function in multiple ways and may be capable of producing other models of cardiac irregularities (e.g. arrhythmias, abnormal levels of regurgitant flow in the atrioventricular junction, etc.).
The mechanisms behind congenital heart defects (CHDs) are largely unclear, and biomechanical forces likely play a role during the development of CHDs. This project aims to develop new technology (optical pacing) capable of perturbing biomechanical forces in the heart in order to elucidate the complex interplay between structure and function in the developing heart in vivo. Better understanding of the origins and progression of congenital heart defects can potentially lead to better prediction of outcomes, and earlier, more effective treatments.
|Blech-Hermoni, Yotam; Sullivan, Connor B; Jenkins, Michael W et al. (2016) CUG-BP, Elav-like family member 1 (CELF1) is required for normal myofibrillogenesis, morphogenesis, and contractile function in the embryonic heart. Dev Dyn 245:854-73|
|Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36|
|Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu et al. (2015) Using optical coherence tomography to rapidly phenotype and quantify congenital heart defects associated with prenatal alcohol exposure. Dev Dyn 244:607-18|
|Peterson, Lindsy M; Gu, Shi; Jenkins, Michael W et al. (2014) Orientation-independent rapid pulsatile flow measurement using dual-angle Doppler OCT. Biomed Opt Express 5:499-514|
|Wang, Yves T; Gu, Shi; Ma, Pei et al. (2014) Optical stimulation enables paced electrophysiological studies in embryonic hearts. Biomed Opt Express 5:1000-13|
|Ma, Pei; Wang, Yves T; Gu, Shi et al. (2014) Three-dimensional correction of conduction velocity in the embryonic heart using integrated optical mapping and optical coherence tomography. J Biomed Opt 19:76004|
|Wang, Yves T; Gu, Shi; Rollins, Andrew M et al. (2013) Optical mapping of optically paced embryonic hearts. Conf Proc IEEE Eng Med Biol Soc 2013:1623-6|
|Jenkins, Michael W; Wang, Y T; Doughman, Y Q et al. (2013) Optical pacing of the adult rabbit heart. Biomed Opt Express 4:1626-35|
|Peterson, L M; McPheeters, M; Barwick, L et al. (2012) Altering embryonic cardiac dynamics with optical pacing. Conf Proc IEEE Eng Med Biol Soc 2012:1382-5|