Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus

项目摘要 脑室内出血（GMH-IVH）是导致发病的重要原因， 早产儿的死亡率，在美国每年有14，000例新病例。百分之四十的严重GMH- IVH婴儿预后差，25%的出血后脑积水需要长期治疗 (PHH)是北美地区脑积水最常见的原因。虽然IVH和PHH之间的联系是 虽然PHH的基础病理生理学已被公认，但尚未完全了解， 预防性治疗。IVH后心室中释放的血液分解产物铁和血红蛋白 导致纤毛衬里的室管膜损伤并引起脑积水。虽然铁螯合治疗减少了 对于IVH后脑积水，尚不清楚铁和血红蛋白如何导致脑室扩大， 室管膜损伤IVH后血红蛋白-触珠蛋白受体CD 163的表达增加， 心室室管膜，并可能代表细胞铁摄取导致损伤的重要途径。我们有 还证明了唯一已知的细胞铁输出蛋白ferroportin 1（FP 1）在室管膜上表达 细胞，随后上调响应IVH。室管膜由活动纤毛排列， 涉及脑脊液流动和初级纤毛，其调节和指导神经前体细胞在 心室表面运动性和原发性纤毛功能障碍的遗传模型显示出异常的 脑脊液（CSF）流量和脑积水;然而，纤毛功能尚未在PHH中进行评估。我们 已经证明IVH后铁诱导的纤毛损伤和功能障碍。这项建议的目的是 确定铁诱导的室管膜损伤、纤毛功能障碍和脑积水之间的关系。我们将 测试中心假设，即铁通过CD 163转运和铁通过FP 1输出的抑制， 心室表面导致室管膜、室管膜下区（SVZ）和纤毛损伤， 室管膜发育和局部CSF流动，最终导致脑积水。我们将测试我们的假设在 1）确定CD 163是否介导铁诱导的室管膜和SVZ损伤， GMH-IVH后脑积水。2)确定FP 1在铁介导的室管膜和SVZ损伤中的作用， III级和IV级GMH-IVH后出现脑积水。3)确定铁螯合作用在脑脊液流出中的作用， GMH-IVH和确定纤毛功能障碍如何有助于铁介导的室管膜细胞损伤，CSF流量和 通过使出生后室管膜纤毛运动失活而引起脑积水。如果成功，这些实验将提供 预防PHH的新靶点，并为纤毛功能障碍如何促进PHH提供新的见解。 脑积水

Project Summary Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a significant cause of morbidity and mortality in preterm infants, with 14,000 new cases each year in the United States. Forty percent of severe GMH- IVH infants have poor outcomes and 25% require long-term treatment for post-hemorrhagic hydrocephalus (PHH), the most common cause of hydrocephalus in North America. Although the link between IVH and PHH is well established, the underlying pathophysiology of PHH is incompletely understood and there are no preventative treatments. Blood breakdown products, iron and hemoglobin, released in the ventricle after IVH result in injury to the cilia-lined ependyma and cause hydrocephalus. While treatment with iron chelation reduces hydrocephalus after IVH, it is unknown how iron and hemoglobin result in ventricular enlargement and ependymal injury. Expression of the hemoglobin-haptoglobin receptor, CD163, is increased after IVH in the ventricular ependyma and may represent an important route of cellular iron uptake leading to injury. We have also demonstrated that the only known cellular iron exporter, ferroportin 1 (FP1), is expressed on ependymal cells and subsequently upregulated in response to IVH. The ependyma is lined by motile cilia, which are implicated in cerebrospinal fluid flow, and primary cilia, which regulate and direct neural precursor cells at the ventricular surface. Genetic models of both motile and primary cilia dysfunction demonstrate abnormal cerebrospinal fluid (CSF) flow and hydrocephalus; however, cilia function has not been evaluated in PHH. We have demonstrated iron-induced cilia injury and dysfunction after IVH. The objective of this proposal is to determine the relationship between iron-induced ependymal injury, cilia dysfunction and hydrocephalus. We will test the central hypothesis that iron transport through CD163 and inhibition of iron export through FP1 at the ventricular surface results in ependymal, subventricular zone (SVZ) and cilia injury, leading to defects in ependymal development and regional CSF flow, culminating in hydrocephalus. We will test our hypothesis in the following Specific Aims: 1) Determine whether CD163 mediates iron-induced ependymal and SVZ injury and hydrocephalus after GMH-IVH. 2) Determine the role of FP1 in iron-mediated ependymal and SVZ injury and hydrocephalus after grade III and grade IV GMH-IVH. 3) Determine the role of iron chelation in CSF outflow after GMH-IVH and identify how cilia dysfunction contributes to iron-mediated ependymal cell injury, CSF flow and hydrocephalus by inactivating postnatal ependymal cilia movement. If successful, these experiments will provide novel targets for prevention of PHH and provide new insight into how cilia dysfunction contributes to hydrocephalus.