Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality

项目摘要（减少到适合< 30行） 本提案的目的是开发一种非接触式、全光学成像技术来映射弹性模量 以及涉及胚胎发育关键方面的力。拟议 该技术基于布里渊光谱学和光学相干断层扫描（OCT）的组合， 用于获得神经管闭合（NTC）过程中涉及的生物力学因素的基本理解 在正常和病理情况下，使用建立和充分验证的鼠神经管缺陷（NTD）模型。 NTD是人类第二大常见的结构性出生缺陷，影响超过50万例妊娠 仅在美国每年就有约2400例妊娠。NTC包括一系列复杂的 因此，涉及组织运动的过程由力驱动。然而，NTC的生物物理学，即 组织力和刚度之间的相互作用，仍然知之甚少，主要是因为次优 测量技术在过去的几年里，我们的团队开发了先进的成像技术; OCT用于发育胚胎的结构/功能成像，布里渊显微镜用于机械映射 组织，当结合在一起时，可以是变革性的，以阐明生物力学的基础， NTD的发展。我们的长期目标是阐明如何控制NTC的机械性能， 可以操纵发育中的胚胎以确保处于危险中的胚胎中的适当神经发育。我们的中央 有一种假说认为，在遗传易感的胚胎中，NTC的失败导致NTD是由机械介导的， 可以用布里渊-OCT成像的融合神经褶皱边缘的改变和异常力 多模态。为了验证这一中心假设，我们的目标是将联合收割机OCT、布里渊显微镜和 分析建模，以建立一个平台技术，以映射弹性模量和力，在开发鼠标 胚胎在我们对NTC生物力学的理解中，填补一个重大数据缺口的研究前提是 得到了有力的初步数据支持。该提案是以高度的研究严谨性开发的：我们的目标1将侧重于 关于布里渊显微镜测量活胚胎组织的先进发展。组合 将在目标2中开发和测试布里渊/OCT仪器。最后，在目标3中，我们将检验以下假设： 机械性能和力严重介导遗传易感性或致畸原诱导的NTD。到 为了实现我们的目标，我们组建了一个多学科团队，拥有OCT（Larin），布里渊散射（Brillouin） 技术（Scarcelli），生物力学建模（Aglyamov），发育生物学和NTD疾病 （Finnell）.成功完成拟议的研究计划将产生一个独特的平台 技术，这将使机械表型与基因和蛋白质相关的研究成为可能 全球开发的表达谱，以提供对整个 导致NTD和潜在其他复杂先天性畸形的事件的发育谱。

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.