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（由适用提供）：这项研究的总体目的是开发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关，以了解乙醇（ETOH）和尼古丁（NIC）（NIC）对胚胎脑发育的影响。这些物质的孕产妇暴露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共施加。然而，对NIC和ETOH的胎儿效应的研究非常有限，并且对胎儿发育的分子机制，尤其是大脑的结合作用，对大脑的结合作用很少。因此，通过开发能够实时对发育脑的纵向分析的高分辨率成像技术来理解ETOH和NIC之间的效果之间的相互作用的迫切需要。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发育的互动作用。在该提案中，我们将研究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，并通过实施创新的高分辨率胚胎脑成像和动态定量分析方法，并采用我们开发的动态定量分析方法。我们采用了基于OCT的基于OCT的方法，用于在子宫内的子宫成像和子宫中小鼠胎儿的纵向表型分析。在这里，我们建议进一步开发纵向脑成像和分析的技术和方法。当神经元干细胞引起成人大脑的大多数神经元时，这项研究的重点是第二个孕期的发育期。该提议的核心假设是EtoH和NIC在胎儿脑发育中具有部分拮抗作用。通过成功实现该提案，我们将建立一种活小鼠胚胎脑成像方法，将开发一组方案和详细的评估，以定量地表征动态胚胎脑发育，并通过细胞分辨率进行调查，并研究ETOH和NIC是否协同化以破坏大脑发育或暴露了部分拮抗作用。我们还将评估使用烟碱受体拮抗剂和激动剂的可行性，以防止ETOH和NIC的个体和综合作用。因此，从基本生物学和致畸的观点中研究这种效果非常重要，因为它可能对新型和创新疗法的发展具有特别的影响，以逆转畸形学。