Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality

使用布里渊-OCT 多模态进行神经管发育的生物力学

• 批准号: 10194569
• 负责人: RICHARD H. FINNELL
• 金额: $ 61.38万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194569
• 关键词: 3-Dimensional; Acoustics; Address; Advanced Development; Affect; Aftercare; Animals; Biochemical; Biological Models; Biomechanics; Biophysics; Blood flow; Carbon Dioxide; Clinical; Complex; Congenital Abnormality; Congenital Heart Defects; Cost Savings; Data; Development; Developmental Biology; Disease; Drug or chemical Tissue Distribution; Economics; Embryo; Embryonic Development; Ensure; Environment; Event; Failure; Frequencies; Functional Imaging; Future; Gene Expression; Genetic; Genetic Predisposition to Disease; Goals; Gold; Grant; Health Care Costs; Human; Image; Imaging Device; Imaging technology; Impairment; Incubators; Intervention; Light; Maps; Measurement; Measures; Mechanics; Mediating; Methods; Microscope; Microscopy; Modality; Modeling; Modulus; Monitor; Morphogenesis; Morphology; Motion; Mus; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Optical Coherence Tomography; Optics; Pathologic; Phenotype; Pregnancy; Process; Public Health; Regulation; Research; Resistance; Resolution; Risk; Role; Series; Spectrum Analysis; Structural Congenital Anomalies; Structural defect; Structure; Techniques; Technology; Temperature; Teratogens; Testing; Time; Tissues; United States; base; biomechanical model; cost; embryo tissue; heart function; image guided; in vivo; instrument; interest; light scattering; mechanical force; mechanical properties; mouse model; multidisciplinary; multimodality; mutant; neurodevelopment; new technology; novel; optical imaging; programs; protein expression; social; tool

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.

项目摘要（减少到 < 30 行） 该提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量图 以及参与胚胎发育关键方面的力量，具有高 3D 分辨率。拟议的 技术基于布里渊光谱和光学相干断层扫描 (OCT) 的结合，将 用于获得对神经管闭合 (NTC) 过程中涉及的生物力学因素的基本了解 在正常和病理情况下，使用已建立且经过充分验证的小鼠神经管缺陷（NTD）模型。 NTD 是人类第二常见的结构性出生缺陷，影响超过 50 万次妊娠 全世界每年约有 2400 例怀孕。 NTC 包括一系列复杂的 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； 用于发育胚胎结构/功能成像的 OCT 和用于机械绘图的布里渊显微镜 组织，当组合在一起时，可以变革性地阐明其背后的生物力学 NTD 的发展。我们的长期目标是阐明机械性能如何控制 NTC 可以对发育中的胚胎进行操纵，以确保有风险的胚胎中神经的正常发育。我们的中央 假设是 NTC 失败导致遗传易感胚胎中的 NTD 是由机械介导的 融合神经褶皱边缘的改变和异常力，可通过布里渊 OCT 成像 多模态。为了检验这一中心假设，我们的目标是将 OCT、布里渊显微镜和 分析建模以建立平台技术来绘制发育小鼠的弹性模量和力 胚胎。填补我们对 NTC 生物力学理解的重大数据空白的研究前提是 得到了强有力的初步数据的支持。该提案的制定具有高度的研究严谨性：我们的目标 1 将重点关注 布里渊显微镜测量活胚胎组织的先进发展。一个组合 布里渊/OCT 仪器将在目标 2 中开发和测试。最后，在目标 3 中，我们将测试以下假设： 机械特性和力对遗传易感性或致畸性诱发的 NTD 具有关键作用。到 为了实现我们的目标，我们组建了一支多学科团队，拥有OCT（拉林）、布里渊等领域的专业知识 技术 (Scarcelli)、生物力学建模 (Aglyamov) 以及发育生物学和 NTD 疾病 （芬内尔）。拟议研究计划的成功完成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 在全球范围内开发表达谱，以便提供对整个表达谱的机械理解 导致 NTD 和潜在其他复杂先天畸形的发育事件。