Optical Coherence Tomography to Study Effect of Poly - Drug Exposure on Fetal Brain Development

 描述（由申请方提供）：本研究的总体目标是开发一种基于光学相干断层扫描（OCT）的高分辨率小鼠胚胎脑成像和分析方法，并将该方法与分子分析相结合，以了解乙醇（EtOH）和尼古丁（NIC）对胚胎脑发育的影响之间的相互作用。母亲接触这些物质与胎儿生长迟缓和神经毒性有关，这些毒素通常在怀孕期间被共同滥用。然而，关于NIC和EtOH对胎儿的联合作用的研究非常有限，并且它们对胎儿发育的分子机制的联合作用，特别是对大脑的影响，知之甚少。因此，迫切需要通过开发能够对发育中的大脑进行实时纵向分析的高分辨率成像技术来了解EtOH和NIC的影响之间的相互作用。有趣的是，我们最近的研究表明，EtOH和NIC对胎儿神经干细胞的发育产生相互拮抗作用。在这项提议中，我们将调查这些毒素是否确实对活小鼠胚胎中的胚胎脑发育具有拮抗或协同作用，并实施我们开发的创新的高分辨率胚胎脑成像和动态定量分析方法。我们开创了基于OCT的子宫内活体成像和子宫内小鼠胎儿纵向表型分析方法。在这里，我们建议进一步发展纵向脑成像和分析的技术和方法。这项研究的重点是中期三个月相当的发展时期，当神经元干细胞产生成人大脑的大部分神经元。该建议的中心假设是EtOH和NIC在胎儿脑发育中具有部分拮抗作用。通过该提案的成功完成，我们将建立一种活的小鼠胚胎脑成像方法，将开发一套方案和详细的评估，以定量表征动态胚胎脑发育与细胞分辨率，并将调查EtOH和NIC是否协同破坏脑发育或表现出部分拮抗作用。我们还将评估使用烟碱受体拮抗剂和激动剂预防EtOH和NIC单独和联合作用的可行性。因此，从基础生物学和致畸的角度来看，研究这种效应是非常重要的，因为它可能对开发用于逆转畸形学的新型和创新疗法具有特别重要的影响。

 DESCRIPTION (provided by applicant): The overall objective of this study is to develop an optical coherence tomography (OCT) based high- resolution mouse embryonic brain imaging and analysis approach, and to use this method in correlation with molecular analysis to understand the interplay between ethanol (EtOH) and nicotine (NIC) effects on embryonic brain development. Maternal exposures to these substances are linked to fetal growth retardation and neurotoxicity, and these toxins often co-abused during pregnancy. However, studies on the combined fetal effects of NIC and EtOH are very limited and their combined effects on molecular mechanisms of fetal development, particularly the brain, are poorly understood. Therefore, there is a critical need to understand the interplay between the effects of EtOH and NIC via development of high-resolution imaging technique capable of live longitudinal analysis of developing brain. Intriguingly, our recent studies suggested that EtOH and NIC exert mutually antagonistic effects on fetal neuronal stem cells development. In this proposal, we will investigate if these toxins have indeed antagonistic or synergetic effects on embryonic brain development in live mouse embryos with implementation of an innovative higher-resolution embryonic brain imaging and dynamic quantitative analysis approaches, which we develop. We have pioneered OCT-based methodology for live in utero imaging and longitudinal phenotypic analysis of mouse fetuses in utero. Here we propose to further develop both the technology and the methodology for longitudinal brain imaging and analysis. The study is focused on the second trimester- equivalent period of development, when the neuronal stem cells give rise to most of the neurons of the adult brain. The central hypothesis of this proposal is that EtOH and NIC have partially antagonistic effects in fetal brain development. By successful accomplishment of the proposal, we will establish a live mouse embryonic brain imaging approach, will develop a set of protocols and detailed assessments to quantitatively characterize dynamic embryonic brain development with cellular resolution, and will investigate if EtOH and NIC synergize to disrupt the brain development or exhibit partially antagonistic effects. We will also assess the feasibility of using nicotinic receptor antagonists and agonists t prevent the individual and combined effects of EtOH and NIC. Therefore, studying this effect is highly significant from both fundamental biology and teratogenic points of view since it may have particular significant impact for the development of novel and innovative therapies for reversing teratology.