Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality

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PROJECT ABSTRACT (Reduced to fit in < 30 lines) The objective of this proposal is to develop a non-contact, all-optical imaging technology to map elastic moduli and forces involved in critical aspects of embryonic development with high 3D resolution. The proposed technology is based on combined Brillouin spectroscopy and Optical Coherence Tomography (OCT), which will be used to gain fundamental understanding of biomechanical factors involved during neural tube closure (NTC) in normal and pathological cases using established and well validated murine neural tube defect (NTD) models. NTDs are the second most common structural birth defect in humans, affecting upwards of 500,000 pregnancies worldwide and ~ 2400 pregnancies each year in the United States alone. NTC comprises a complex series of processes that involve tissue motion, thus are driven by forces. However, the biophysics of NTC, namely the interplay between tissue forces and stiffness, remains poorly understood, mostly because of sub-optimal measurement techniques. In the past few years, our groups have developed advanced imaging technologies; OCT for structural/functional imaging of developing embryos and Brillouin microscopy for mechanical mapping of tissues, that, when combined, can be transformative to elucidate the biomechanics underlying the development of NTDs. Our long-term goal is to elucidate how mechanical properties controlling NTC in developing embryos can be manipulated to ensure proper neural development in at risk embryos. Our central hypothesis is that failure of NTC leading to NTDs in genetically predisposed embryos is mediated by mechanical alterations and abnormal forces at the edge of the fusing neural folds that can be imaged with Brillouin-OCT multimodality. To test this central hypothesis, our objective is to combine OCT, Brillouin microscopy and analytical modeling to establish a platform technology to map elastic moduli and forces in developing mouse embryos. The research premise of filling a significant data gap in our understanding of NTC biomechanics is supported by strong preliminary data. The proposal is developed with high research rigor: our Aim 1 will focus on the advanced development of Brillouin microscopy to measure live embryonic tissue. A combined Brillouin/OCT instrument will be developed and tested in Aim 2. Finally, in Aim 3 we will test the hypothesis that mechanical properties and forces critically mediate genetically predisposed or teratogen-induced NTDs. To accomplish our objective, we have assembled a multidisciplinary team with expertise in OCT (Larin), Brillouin technology (Scarcelli), biomechanical modeling (Aglyamov), and developmental biology and NTD disorders (Finnell). The successful completion of the proposed research program will produce a unique platform technology, which will enable studies where a mechanical phenotype is correlated with gene and protein expression profiles developed globally, in order to provide mechanistic understanding of the entire developmental spectrum of events leading to NTDs and potentially other complex congenital malformations.