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: 10541341
• 负责人: JOANNE C CONOVER
• 金额: $ 6.03万
• 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/10541341
• 关键词: 3-Dimensional; Address; Apical; Area; Brain; Cell Line; Cerebrospinal Fluid; Childhood; Color; Data; Development; Disease; Embryo; Ependymal Cell; Epithelial; Fetal Development; Human; Hydrocephalus; Immunity; Infection; Influenza; Intraventricular; Intraventricular Injections; Lateral; Link; Maps; Mediating; Modeling; Mus; Neuraminidase; Neuroglia; Neurons; Pathologic; Process; Regenerative capacity; Route; Severities; Subependymal; Surface; Testing; Thinness; Time; Variant; Ventricular; Viral; Virus; Work; course development; lateral ventricle; live cell imaging; monolayer; neurogenesis; postnatal; postnatal development; prenatal; programs; public health relevance; regenerative repair; repaired; stem cell function; stem cell niche; stem cells; subventricular zone; treatment strategy; vector; ventricular system

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.

摘要 细菌和病毒感染都与儿童脑积水有关，并可能影响新生儿 大脑的发育计划。在胎儿发育过程中，干细胞排列在脑室并提供神经元和 脑发育所需的神经胶质细胞；与脑室接触的干细胞也会产生保护性上皮细胞 室管膜细胞的单层。当室管膜细胞沿着脑室形成屏障时，剩下的干细胞 细胞降至室管膜下区，仅保留与大脑接触的细小顶突。 脊髓液。这种独特的排列是沿着外侧壁的干细胞壁龛的特征。 脑室，并支持出生后发育中持续的神经发生。已知某些病毒 优先靶向脑室室管膜细胞衬里，导致结构支撑和屏障的丧失 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 将严重影响干细胞利基的发展和功能。 这项建议的前提是以受控的方式模拟感染，并表征对 感染后脑室-脑室下区干细胞巢修复机制的研究 脑积水。先前的工作在3D(老鼠和人)中绘制侧脑室以确定体积， 曲面面积和曲率在发展过程中会发生变化。来自世系追踪的新数据(多色 载体)和活细胞成像将记录干细胞介导室管膜发生与神经发生 解决正常发育中的干细胞枯竭问题(目标1)。脑室扩大的假说 (脑积水)影响干细胞巢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注射神经氨酸酶后感染后遗症 将检查脑积水、关键发育时间点和干细胞介导修复的潜力。 在检查了一种单一变异型神经氨酸酶、脑积水模型后，真正的感染后 将模拟使用小鼠变种流感的脑积水(目标3)。脑室内、胎盘内和 将评估鼻腔途径以及对脑室-脑室下干细胞利基及其 我们将对功能进行检查。流感诱发感染后的诱发和严重程度假说 脑积水可以通过先前的同种或异种免疫来减轻，也将进行检测。这些研究 将确定感染后脑积水对关键干细胞生态位的影响及其对 再生修复-感染后脑积水的指导性治疗策略。