Disease Mechanisms of Prenatal and Pediatric Acquired Hydrocephalus

产前和儿童获得性脑积水的发病机制

• 批准号: 10600022
• 负责人: JOANNE C CONOVER
• 金额: $ 35.22万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600022
• 关键词: 3-Dimensional; Address; Adhesives; Adult; Anterior; Apical; Area; Brain; Cell Count; Cell Cycle; Cell Differentiation process; Cell Line; Cell surface; Cells; Cerebrospinal Fluid; Childhood; Cleaved cell; Color; Coupled; Data; Development; Disease; Electroporation; Embryo; Embryonic Ventricle; Enzymes; Ependyma; Ependymal Cell; Epithelium; Experimental Designs; Fetal Development; Human; Hydrocephalus; Immunity; Infection; Influenza; Influenza A virus; Injury; Intranasal Administration; Intraventricular; Intraventricular Injections; Label; Lateral; Life; Link; Magnetic Resonance Imaging; Maps; Measures; Mediating; Modeling; Monitor; Mus; Neonatal; Neuraminidase; Neuroglia; Neurons; Pathogenesis; Pathologic; Positioning Attribute; Process; Production; Property; Prosencephalon; Radial; Recovery; Regenerative capacity; Resistance; Resolution; Route; Sampling; Severities; Sialoglycoproteins; Slice; Subependymal; Surface; Testing; Thinness; Time; Variant; Ventricular; Viral; Viral Proteins; Virus; Work; astrogliosis; course development; immune activation; improved; in utero; influenza virus strain; influenzavirus; lateral ventricle; live cell imaging; monolayer; mouse model; neurogenesis; neurovirulence; postnatal; postnatal development; postnatal period; prenatal; programs; public health relevance; reconstruction; regenerative repair; repaired; reparative capacity; response; spatiotemporal; stem cell division; stem cell fate; stem cell function; stem cell niche; stem cell proliferation; stem cells; subventricular zone; treatment strategy; vector; ventricular system; young adult

Abstract Infections, both bacterial and viral, have been linked to pediatric hydrocephalus and can impact the nascent brain’s developmental programs. In fetal development, stem cells line the ventricles and provide neurons and glia required for brain development; ventricle-contacting stem cells also generate a protective epithelial monolayer of ependymal cells. As ependymal cells form a barrier wall along the ventricles, the remaining stem cells are relegated to the subependymal zone and retain only a thin apical process in contact with the cerebral spinal fluid. This unique arrangement characterizes the stem cell niche along the lateral walls of the lateral ventricle and supports continued neurogenesis in postnatal development. It is known that certain viruses preferentially target the ependymal cell lining of the ventricles resulting in loss of the structural support and barrier functions provided by the ependymal cells. Infection during periods of ependymogenesis and neurogenesis would critically impact the development and function of the stem cell niche. The premise of this proposal is to model infection in a controlled manner and characterize damage to, and reparative mechanisms of, the ventricular-subventricular zone stem cell niche over the course of post-infectious hydrocephalus. Previous work mapped the lateral ventricles in 3D (mouse and human) to determine volume, surface area and curvature changes over the course of development. New data from lineage tracing (multi-color vectors) and live cell imaging will document stem cell-mediated ependymogenesis versus neurogenesis and address stem cell depletion in normal development (Aim 1). The hypothesis that enlarged ventricles (hydrocephalus) impact stem cell niche functions and compromise neurogenesis will first be tested using a neurovirulent component of influenza, neuraminidase, which is known to cause hydrocephalus in mice (Aim 2). After intraventricular injection of neuraminidase in embryonic and postnatal mice, sequelae of post-infectious hydrocephalus, critical developmental time points and potential for stem cell-mediated repair will be examined. Following examination of a univariant, neuraminidase, hydrocephalus model, bona fide post-infectious hydrocephalus using a mouse variant of influenza will be modeled (Aim 3). Intraventricular, intraplacental and intranasal routes will be assessed and the impact on the ventricular-subventricular stem cell niche and its functions will be examined. The hypothesis that induction and severity of influenza-induced post-infectious hydrocephalus can be mitigated by prior homologous or heterologous immunity will also be tested. These studies will define the impact that post-infectious hydrocephalus has on a critical stem cell niche and its capacity for regenerative repair – guiding treatment strategies for post-infectious hydrocephalus.

抽象的 细菌和病毒感染与小儿脑积水有关，并可能影响新生儿 大脑的发育程序。在胎儿发育过程中，干细胞排列在心室中并提供神经元和 大脑发育所需的神经胶质细胞；心室接触干细胞也产生保护性上皮细胞 单层室管膜细胞。当室管膜细胞沿着心室形成屏障壁时，剩余的干细胞 细胞被降级到室管膜下区，仅保留一个薄的顶端过程与大脑接触 脊髓液。这种独特的排列表征了沿着侧脑室侧壁的干细胞生态位。 心室并支持出生后发育中持续的神经发生。众所周知，某些病毒 优先针对心室室管膜细胞内壁，导致结构支撑和屏障丧失 室管膜细胞提供的功能。室管膜发生和神经发生期间的感染 将严重影响干细胞生态位的发育和功能。 该提案的前提是以受控方式对感染进行建模并描述损害的特征，以及 感染后过程中心室-心室下区干细胞生态位的修复机制 脑积水。之前的工作绘制了 3D 侧脑室（小鼠和人类）以确定体积， 表面积和曲率在开发过程中发生变化。来自谱系追踪的新数据（多色 载体）和活细胞成像将记录干细胞介导的室管膜发生与神经发生和 解决正常发育过程中的干细胞耗竭问题（目标 1）。心室扩大的假说 （脑积水）影响干细胞生态位功能和损害神经发生将首先使用 流感的神经毒性成分神经氨酸酶，已知会导致小鼠脑积水（目标 2）。 胚胎和出生后小鼠脑室内注射神经氨酸酶后，感染后的后遗症 将检查脑积水、关键发育时间点和干细胞介导的修复潜力。 对单变量、神经氨酸酶、脑积水模型进行检查后，真正的感染后 将使用小鼠流感变种对脑积水进行建模（目标 3）。脑室内、胎盘内和 将评估鼻内途径以及对心室-心室下干细胞生态位及其影响 将检查功能。流感引起的感染后的诱发和严重程度的假设 脑积水可以通过先前的同源或异源免疫来减轻，也将进行测试。这些研究 将定义感染后脑积水对关键干细胞生态位及其能力的影响 再生修复——指导感染后脑积水的治疗策略。