An ex-vivo placental perfusion system to study materno-fetal biology

用于研究母胎生物学的离体胎盘灌注系统

• 批准号: 7843099
• 负责人: Alexandre Bonnin
• 金额: $ 24.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843099
• 关键词: 5-Hydroxytryptophan; Address; Affect; Age; Anabolism; Attention; Biological Assay; Biological Models; Biology; Biomedical Engineering; Blood Circulation; Brain; Child; Collaborations; Collection; Development; Developmental Process; Discipline; Disease; Double-Stranded RNA; Embryo; Engineering; Fetus; Functional disorder; Gene Expression; Genetic Models; Genetic Predisposition to Disease; Goals; Grant; Harvest; Heterogeneity; High Pressure Liquid Chromatography; Hormones; Hydroxyindoleacetic Acid; Immune; Immune response; Immunity; Injection of therapeutic agent; Interleukin-1; Kynurenine; Laboratories; Lead; Life; Liquid substance; Measures; Metabolic; Metabolic Pathway; Metabolism; Methaqualone; Microfluidics; Molecular; Mothers; Mus; Nature; Neurobiology; Neurotransmitters; Organ; Output; Pathway interactions; Perfusion; Pharmaceutical Preparations; Phase; Placenta; Play; Poly I-C; Pregnancy; Prosencephalon; Reading; Receptor Gene; Regulation; Research; Risk; Role; Sampling; Schools; Serotonin; Side; Staging; Structure; System; Techniques; Technology; Testing; Time; Tryptophan; Tryptophan Metabolism Pathway; autism spectrum disorder; base; chemokine; critical period; cytokine; design; fetal; in utero; in vivo; innovation; insight; neurochemistry; neuropsychiatry; new technology; offspring; prenatal; prototype; public health relevance; relating to nervous system; serotonin receptor; stressor; technology development

DESCRIPTION (provided by applicant): Research to Address the Heterogeneity in Autism Spectrum Disorders (ASD) Project title: An ex-vivo placental perfusion system to study materno-fetal biology. This grant will focus on developing and validating a model system to examine the effects of alterations in materno-fetal interactions on fetal brain development. We propose that the impact of maternal immune challenges and stressors on fetal brain development is a direct consequence of altered materno-fetal interactions taking place in the placenta. Circulating maternal tryptophan metabolism in the placenta is known to be required for protecting the fetus from maternal immunity. Our preliminary results suggest that, during an early critical period of gestation, an alternative pathway of tryptophan placental metabolism also provides serotonin to the fetal circulation and therefore may be critical for normal fetal brain wiring. Advancing a new ex vivo dual perfusion model system proposed here will enable us to test the possibility that maternal immune challenges directly impact multiple placental metabolic pathways for Trp disrupting fetal supply of 5-HT and ultimately brain wiring in utero. Since placental metabolic functions change during pregnancy, we hypothesize that the degree to which maternal factors impact fetal brain development will depend on a combination of timing, nature of the challenges and also genetic susceptibility of the mother and offspring. Our ex vivo model system will provide a unique way to dissect the effect of each factor on tryptophan placental metabolism and subsequently its contribution to impacting neurobiological functions relevant to ASD such as fetal brain circuits formation. The use of mouse placentas will enable us to test the impact of altered placental metabolism in a wide array of genetic models relevant to ASD and at different stages of gestation. This is a critical advance, as it provides unique opportunities to determine how maternally derived neurotransmitters, cytokines, hormones and drugs impact the development of 5HT-relevant and other circuits that have been implicated in ASD. PUBLIC HEALTH RELEVANCE: Maternal-fetal interactions during the prenatal period are essential for brain development in the child. Maternal illness which increases the risk for neuropsychiatric disorders, including ASD, may impair these interactions. We propose to design and implement a new technology that will provide unique opportunities to determine how maternally derived molecules such as neurotransmitters, cytokines, hormones and drugs reach the fetal brain and impact the development of circuits that have been implicated in ASD.

描述（由申请人提供）：解决自闭症谱系障碍异质性（ASD）项目标题的研究：研究Materno-Fetal生物学的前体内胎盘灌注系统。该赠款将着重于开发和验证模型系统，以检查Materno-Fetal相互作用对胎儿脑发育的变化的影响。我们建议，母体免疫挑战和压力源对胎儿脑发育的影响是胎盘中发生的Materno-Fetal相互作用改变的直接结果。已知胎盘中循环的孕妇色氨酸代谢是保护胎儿免受母体免疫力所必需的。我们的初步结果表明，在妊娠的关键早期，色氨酸胎盘代谢的另一种途径也为胎儿循环提供了5-羟色胺，因此对于正常的胎儿脑接线至关重要。推进此处提出的新的离体双重灌注模型系统将使我们能够测试母体免疫挑战直接影响多种胎盘代谢途径，以破坏胎儿供应5-HT的胎儿供应，并最终在子宫内进行大脑接线。由于胎盘代谢功能在怀孕期间发生变化，因此我们假设产妇因素影响胎儿脑发育的程度取决于时间的结合，挑战性质以及母亲和后代的遗传敏感性。我们的离体模型系统将提供一种独特的方法来剖定每个因素对色氨酸胎盘代谢的影响，并随后其对影响与ASD相关的神经生物学功能的贡献，例如胎儿脑回路的形成。小鼠胎盘的使用将使我们能够在与ASD相关的广泛遗传模型和妊娠的不同阶段测试胎盘代谢改变的影响。这是一个关键的进步，因为它提供了独特的机会来确定母体衍生的神经递质，细胞因子，激素和药物如何影响5HT相关的5HT相关和其他与ASD有关的电路的发展。 公共卫生相关性：产前期间产妇的互动对于儿童的大脑发育至关重要。孕产妇疾病增加了包括ASD在内的神经精神疾病的风险，可能会损害这些相互作用。我们建议设计和实施一项新技术，该技术将提供独特的机会来确定诸如神经递质，细胞因子，激素和药物等母体衍生的分子如何到达胎儿大脑，并影响ASD中涉及的电路的发展。