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

光学相干断层扫描研究多药暴露对胎儿大脑发育的影响

• 批准号: 9199561
• 负责人: Kirill V Larin
• 金额: $ 34.58万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199561
• 关键词: 3-Dimensional; Abdomen; Acceleration; Acute; Adult; Agonist; Algorithms; Anatomy; Biology; Blood; Blood Vessels; Blood flow; Brain; Brain imaging; Cerebellum; Cerebrovascular system; Cerebrum; Consumption; Contrast Media; Control Groups; Development; Dose; Drug Delivery Systems; Embryo; Embryonic Development; Environmental Risk Factor; Ethanol; Exhibits; Exposure to; Fetal Development; Fetal Growth Retardation; Fetus; Growth; Histologic; Horns; Human; Image; Image Analysis; Imaging Techniques; Individual; Innovative Therapy; Knowledge; Lasers; Lead; Link; Magnetic Resonance Imaging; Maps; Maternal Exposure; Measurement; Measures; Mental Retardation; Methodology; Methods; Mission; Molecular; Molecular Analysis; Mus; Neurons; Nicotine; Nicotinic Receptors; Optical Coherence Tomography; Organ; Pathway interactions; Pharmacology; Phenotype; Pregnancy; Process; Protocols documentation; Public Health; Reporting; Research; Research Personnel; Resolution; Second Pregnancy Trimester; Source; Speed; Stomach; Surgical incisions; System; Technology; Teratogens; Teratology; Testing; Time; Toxin; United States National Institutes of Health; Uterus; Vascularization; Woman; base; critical period; disability; drug of abuse; fetal; high resolution imaging; imaging approach; imaging modality; imaging study; in utero; in vivo; indexing; innovation; longitudinal analysis; nerve stem cell; neurotoxic; neurotoxicity; non-invasive imaging; novel therapeutics; prevent; public health relevance; response

 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.

 描述（由申请人提供）：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，并使用该方法与分子分析相结合来了解两者之间的相互作用乙醇 (EtOH) 和尼古丁 (NIC) 对胚胎大脑发育的影响 母亲接触这些物质与胎儿生长迟缓和神经毒性有关，并且这些毒素经常在怀孕期间同时滥用。然而，关于 NIC 和 EtOH 对胎儿的综合影响的研究非常有限，而且它们对胎儿发育（特别是大脑）的分子机制的综合影响知之甚少，因此，迫切需要了解 EtOH 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 对胎儿神经元干细胞的发育具有相互拮抗的作用。通过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，毒素确实对活体小鼠胚胎的胚胎脑发育具有拮抗或协同作用。在此，我们建议进一步开发纵向脑成像和分析的技术和方法。这项研究的重点是妊娠中期的神经干发育时期。该提案的核心假设是，EtOH 和 NIC 在胎儿大脑发育中具有部分拮抗作用。通过该提案的成功完成，我们将建立一种活体小鼠胚胎脑成像方法。 ，将开发一套协议和详细评估，以细胞分辨率定量表征动态胚胎大脑发育，并将研究 EtOH 和 NIC 是否协同作用以破坏大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的可行性。拮抗剂和激动剂不能防止 EtOH 和 NIC 的单独作用和联合作用，因此，从基础生物学和致畸的角度来看，研究这种作用都非常重要，因为它可能对逆转畸形的新颖和创新疗法的开发具有特别重要的影响。 。