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: 10391098
• 负责人: Kirill V Larin
• 金额: $ 60.97万
• 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/10391098
• 关键词: 3-Dimensional; Acute; Adhesions; Adult; Alcohol consumption; Alcohols; Algorithms; Animals; Arteries; Attenuated; Behavior; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain imaging; Brain region; Capillary Permeability; Cell Count; Cells; Cephalic; Cerebrovascular system; Companions; Complex; Data; Development; Embryo; Endothelial Cells; Endothelium; Ethanol; Etiology; Exposure to; Fenestrated Capillary; Fetal Alcohol Exposure; Fetal Growth; Fetus; Fluorescence; Fluorescence Microscopy; Funding; Growth; Hemorrhage; Human; Image; Imaging Device; Imaging technology; Immune; Individual; Inflammation Mediators; Inflammatory; Interleukin-12; Intervention; Knowledge; Light; Link; Maternal Exposure; Mediating; Methods; Microglia; Microscopy; Mission; Modality; Modeling; Molecular; Multi-modal optical imaging; Multimodal Imaging; Mus; Nicotine; Optical Coherence Tomography; Peer Review; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Positioning Attribute; Pregnancy; Proteins; Public Health; 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; base; blood vessel development; cell motility; cerebral capillary; cerebral microvasculature; computerized data processing; critical period; disability; fetal; fetal stem cell; high resolution imaging; imaging platform; in utero; innovation; instrument; interleukin-21; intravital imaging; macromolecule; middle cerebral artery; monocyte; nanoparticle; nerve stem cell; neurogenesis; neuroregulation; new technology; nicotine exposure; nicotine use; novel; nutrition; optical imaging; perineural; polysubstance use; pre-clinical; prenatal; prevent; response; stem cell niche; stem cell proliferation; 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

项目总结