Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality

项目摘要(缩小到适合&lt；30行) 该方案的目标是开发一种非接触式、全光学成像技术来绘制弹性模数 以及涉及胚胎发育关键方面的高3D分辨率的力。建议数 这项技术基于布里渊光谱和光学相干层析成像(OCT)相结合，这将 用于基本了解神经管闭合(NTC)过程中涉及的生物力学因素 在正常和病理情况下，使用已建立和验证良好的小鼠神经管缺陷(NTD)模型。 NTDS是人类第二种最常见的结构性出生缺陷，影响了超过50万名孕妇 全球每年约有2400例怀孕，仅美国就有2400例。全国过渡委员会由一系列复杂的 因此，涉及组织运动的过程是由力驱动的。然而，NTC的生物物理学，即 组织力和僵硬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用于发育中胚胎的结构/功能成像和布里渊显微镜用于机械测绘 这些组织，当结合在一起时，可以变革性地阐明 非专利药品的开发。我们的长期目标是阐明机械性能是如何控制NTC的 发育中的胚胎可以被操纵，以确保处于危险状态的胚胎中有适当的神经发育。我们的中央 假设NTC的失效导致遗传易感胚胎中的NTDS是由机械因素介导的。 融合神经皱折边缘的变化和异常力可以用布里渊-OCT成像 多模式。为了验证这一中心假设，我们的目标是将OCT、布里渊显微镜和 建立开发鼠标弹性模数和力映射平台技术的解析建模 胚胎。填补我们对NTC生物力学理解中的重大数据空白的研究前提是 受强劲的初步数据支撑。该提案是在高度严谨的研究基础上制定的：我们的目标1将专注于 关于布里渊显微镜测量活胚胎组织的高级发展。合并后的 布里渊/OCT仪器将在目标2中开发和测试。最后，在目标3中，我们将检验假设 机械性能和力对遗传易感性或致畸剂诱导的神经管畸形起关键作用。至 为了实现我们的目标，我们在布里渊的OCT(拉林)组建了一支拥有专业知识的多学科团队 技术(Scarcelli)、生物力学建模(Agaramov)、发育生物学和NTD障碍 (芬内尔)拟议的研究计划的成功完成将产生一个独特的平台 技术，这将使研究机械表型与基因和蛋白质相关 全球开发的表达简档，以便提供对整个 导致NTDS和其他可能的复杂先天性畸形的事件的发育范围。

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.