Multimodal Optical Imaging on the Effect of Maternal Polysubstance Exposure on Fetal Brain Microvessel Function

多模态光学成像对母体多物质暴露对胎儿脑微血管功能影响的研究

• 批准号: 10704724
• 负责人: Kirill V Larin
• 金额: $ 65.36万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704724
• 关键词: 3-Dimensional; Acute; Adhesions; Adult; Alcohol consumption; Alcohols; Algorithms; Animals; Arteries; Attenuated; Behavior; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Capillary Permeability; Cell Count; Cells; Cephalic; Cerebrovascular system; Circulation; Companions; Complex; Data; Development; Embryo; Endothelial Cells; Endothelium; Ethanol; Etiology; Exposure to; Fenestrated Capillary; Fetal Alcohol Exposure; Fetus; Fluorescence; Fluorescence Microscopy; Funding; Growth; Hemorrhage; Human; Image; Imaging Device; Imaging technology; Immune; Individual; Infiltration; Inflammation Mediators; Inflammatory; Interleukin-12; Intervention; Invaded; Knowledge; Leptomeninges; Light; Link; Maternal Exposure; Mediating; Methods; Microglia; Microscopy; Mission; Modeling; Molecular; Multi-modal optical imaging; Multimodal Imaging; Mus; Nicotine; Optical Coherence Tomography; Peer Review; Penetration; Peripheral; Permeability; Pharmaceutical Preparations; Physiological; Physiology; Positioning Attribute; Pregnancy; Proteins; Public Health; Publications; Publishing; Reporter; Reporting; Research; Residual state; Resolution; Sampling; Specificity; Structure; Surface; Teratogens; Testing; Time; Toxin; Transgenic Mice; United States National Institutes of Health; Uterus; Vascular Permeabilities; Vascular blood supply; Ventricular; Ventricular Function; Visualization; alcohol exposure; angiogenesis; blood vessel development; cell motility; cerebral capillary; cerebral microvasculature; computerized data processing; critical period; disability; efficacy evaluation; fetal; fetal stem cell; high resolution imaging; imaging platform; in utero; innovation; instrument; interleukin-21; intravital imaging; macromolecule; meter; middle cerebral artery; migration; monocyte; nanoparticle; nerve stem cell; neurogenesis; neuroregulation; new technology; nicotine exposure; nicotine use; novel; nutrition; optical imaging; perineural; pharmacologic; polysubstance use; pre-clinical; prenatal; prenatal nicotine exposure; prevent; response; stem cell niche; stem cell proliferation; structural imaging; symposium; systemic inflammatory response; tool; trafficking; two-photon

PROJECT SUMMARY The etiology of congenital brain growth anomalies is complex, but prenatal alcohol/ethanol and nicotine exposure (PEE/PNE) are common causal factors in the US and worldwide. Research has mainly focused on the growth deficits in neural stem cells (NSCs) and their progeny following PEE/PNE. However, we recently used high- resolution imaging to document that PEE results in complementary deficits in blood flow in major cranially- directed arteries. During the previous project period, we adapted Optical Coherence Tomography (OCT) to document that both PEE and PNE resulted in a similar loss of blood flow in the efferent peri-neural vascular plexus (PNVP). The PNVP and its companion, the sub-ventricular vascular plexus (SVP), give rise to capillaries that penetrate the parenchyma of the developing brain. In the NSC niche of the fetal ventricular zone (VZ) these give rise to an atypical class of fenestrated capillaries that contain 50-100 nm-sized trans-endothelial windows. The function of capillary fenestration in the fetal brain is unknown. Still, in the adult brain, the presence of fenestrated capillaries in selected circumventricular brain regions facilitates the transfer of systemic macromolecules into the brain, and persistent activation of brain microglia, and in residual neurogenic niches, facilitates neurogenesis. Based on preliminary and published data, we hypothesize that prenatal ethanol will increase brain angiogenesis, capillary fenestration, and microglial immune cell precursor trafficking to the fetal brain. We further hypothesize that prenatal nicotine will potentiate the alcohol-mediated increase in new blood vessel formation in the fetal brain and additively increase capillary permeability and immune cell migration into the NSC niche of the fetal VZ. To test these hypotheses, our team will develop a new sensitive, high-resolution imaging platform (Aim 1) that combines the complementary benefits of OCT and two-photon light-sheet microscopy (2pLSM) for in utero time-resolved structural imaging of fetal brain capillary micro-vessels with molecular specificity. We will also adapt our innovative intravital imaging technology and mouse reporter models to assess the effects of PEE and/or PNE on the dynamic growth of fetal VZ capillaries and their capacity to transfer macromolecules from fetal systemic circulation to the brain (Aim 2) and the adhesion and diapedesis of immune microglial cell precursors into the fetal NSC niche (Aim 3). This proposal will result in innovative high-resolution imaging tools for in utero fetal imaging and enable for the first time, dynamic, time-resolved assessment of capillary permeability and monocyte precursor invasion, to fill a significant gap in our understanding of the genesis of brain growth deficits due to PEE and/or PNE. These studies will also position us to begin to assess the efficacy of novel pharmacological intervention strategies targeted to prevent or reverse the effects of PEE and PNE on fetuses

项目摘要 先天性大脑生长异常的病因很复杂，但是产前酒精/乙醇和尼古丁暴露 （PEE/PNE）是美国和全球的常见因果因素。研究主要集中于增长 小便/pne后神经干细胞（NSC）及其后代的缺陷。但是，我们最近使用了 分辨率成像以记录尿尿会导致主要颅骨流动的互补缺陷 导向动脉。在上一个项目期间，我们将光学相干断层扫描（OCT）调整为 PEE和PNE都会导致表象中神经周围血管的血流损失相似 丛（PNVP）。 PNVP及其同伴，腹膜丛（SVP）产生毛细血管 这渗透到发育中的大脑的实质。在胎儿心室区域（VZ）的NSC小众中 引起一类非典型的毛细管，其中包含50-100 nm大小的跨层窗户。 胎儿大脑中毛细血管的功能尚不清楚。尽管如此，在成年大脑中， 选定的外脑脑区域中的毛细血管促进了全身的转移 大分子进入大脑，脑胶质细胞的持续激活，以及在残留的神经源性壁ches中 促进神经发生。根据初步和已发布的数据，我们假设产前乙醇将 增加脑血管生成，毛细血管发否和小胶质细胞前体运输到胎儿 脑。我们进一步假设，产前尼古丁将增强酒精介导的新血液的增加 胎儿大脑中的血管形成，并增加毛细血管渗透性和免疫细胞迁移到 胎儿VZ的NSC利基市场。为了检验这些假设，我们的团队将开发一个新的敏感，高分辨率 成像平台（AIM 1）结合了OCT和两光片灯页的互补益处 显微镜（2PLSM），用于胎儿时间分辨的胎儿脑毛细管微体液的结构成像 分子特异性。我们还将调整我们创新的内室成像技术和鼠标记者模型 评估小便和/或PNE对胎儿VZ毛细血管动态增长的影响及其能力 将大分子从胎儿全身循环转移到大脑（AIM 2）以及粘附和二子 免疫小胶质细胞前体进入胎儿NSC小众（AIM 3）。 该建议将为子宫胎面成像提供创新的高分辨率成像工具，并启用 第一次，动态的，时间分辨的毛细血管渗透性和单核细胞前体入侵的评估，以填充 我们对由于小便和/或PNE引起的大脑生长缺陷的起源的理解有很大的差距。这些 研究还将使我们开始评估新型药理干预策略的功效 针对防止或扭转小便和pne对胎儿的影响的目标