Cerebrospinal Fluid Dynamics in Posthemorrhagic Hydrocephalus in Neonates

新生儿出血后脑积水的脑脊液动力学

• 批准号: 10213849
• 负责人: John H Zhang
• 金额: $ 34.56万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213849
• 关键词: Acute; Astrocytes; Blood Vessels; Brain hemorrhage; Cerebrospinal Fluid; Choroid Plexus Epithelium; Chronic; Cicatrix; Clinical Management; Data; Development; Drainage procedure; Economic Burden; Epithelial Cells; Erythrocytes; Floor; Fluids and Secretions; Fluorescence; Goals; Heme; Hemorrhage; Hydrocephalus; Impairment; Incidence; Inflammation; Intercellular Fluid; Iron; Iron Overload; Lead; Live Birth; Magnetic Resonance Imaging; Mediating; Modality; Morbidity - disease rate; Neurons; Obstruction; Operative Surgical Procedures; Perinatal subependymal hemorrhage; Peritoneum; Play; Premature Infant; Production; Robin bird; Role; Rupture; Shunt Device; Sodium Bicarbonate; Structure of choroid plexus; Subependymal; Surgical complication; Testing; Therapeutic; Thinness; Tissues; Toxic effect; Tracer; Up-Regulation; Villus; Work; aquaporin 4; astrogliosis; blood cerebrospinal fluid barrier; blood product; caudate nucleus; cerebrospinal fluid flow; cost; effective therapy; glymphatic dysfunction; glymphatic system; injured; innovation; inward rectifier potassium channel; lateral ventricle; mortality; neonate; new therapeutic target; novel; side effect; socioeconomics; symporter; therapeutic target; water flow

Abstract Germinal matrix hemorrhage (GMH) is the bleeding from the thin-walled immature blood vessels in the germinal matrix of pre‑term infants. Post‑hemorrhagic hydrocephalus is a common but severe consequence from GMH. However, there is no effective treatment for this so far but surgical shunting, which causes a huge socioeconomic burden. Thus, to characterize the underlying mechanisms and identify the potential therapeutic targets are of the utmost importance. Cerebrospinal fluid (CSF) is mainly produced from the choroid plexus and reabsorbed by subarachnoid villi and to a greater extent in neonates, through the glymphatic system. GMH results in breakdown of blood products, inflammation and astrogliosis, which can damage periventricular tissues. Tissues responsible for maintaining normal CSF flow dynamics may be injured following GMH, contributing to post-hemorrhagic hydrocephalus. The choroid plexus is specialized for CSF production and regulating the blood-CSF barrier. Iron toxicity from lysed red blood cells after GMH may lead to increased expression of slc4a10, a sodium bicarbonate co-transporter responsible for CSF secretion, and consequent CSF over-secretion at the choroid plexus. Furthermore, glymphatic CSF drainage is postulated to play a great role in neonates, since subarachnoid villi are sparsely distributed, and its function may also be compromised following GMH. The glymphatic system involves astrocyte-mediated CSF-interstitial fluid (ISF) exchange in Virchow-Robin space, which is driven by astrocytic aquaporin-4. In addition, inwardly rectifying potassium channel 4.1 (Kir4.1) works in conjunction with aquaporin-4 in astrocytes for regulating osmotic gradients and consequent water flow, yet its role in glymphatic CSF-ISF exchange has not been established. Astrogliosis from GMH may alter aquaporin-4 and Kir4.1 expression or function, disrupting glymphatic CSF-ISF exchange and consequently reducing CSF reabsorption. Our overall hypothesis is that, following GMH, acute iron overload contributes to CSF overproduction at the choroid plexus by inducing slc4a10 and long-term astrogliosis impairs normal CSF reabsorption through the glymphatic system, leading to post- hemorrhagic hydrocephalus in neonates. To test this hypothesis, we will conduct our study in two specific aims. Specific Aim 1: Determine the role of iron-induced expression of slc4a10 at the choroid plexus after GMH, leading to increased CSF secretion. Specific Aim 2: Determine the role of GMH-induced astrogliosis and consequent Kir4.1 and aquaporin-4 expression in disrupting CSF-ISF exchange and CSF clearance through the glymphatic system.

抽象的 生发基质出血（GMH）是来自薄壁未成熟血管的出血 前婴儿的生发基质。 hemorrhagic脑积水是一种常见但严重的后果 来自GMH。但是，到目前为止尚无有效的治疗方法 社会经济伯恩。这是为了表征基本机制并确定潜在的疗法 目标至关重要。脑脊液（CSF）主要由脉络丛产生 并通过甘氨酸绒毛属的蛛网膜绒毛吸收，并在更大程度上通过乙二醇化系统吸收。 GMH 导致血液产品，感染和星形胶质细胞增多症的细分，这可能会损害周围 组织。 GMH后，负责维持正常CSF流动动力学的组织可能会受伤 造成杀伤后脑积水。脉络丛专门用于CSF生产和 调节血液-CSF屏障。 GMH后定义的红细胞的铁毒性可能导致增加 SLC4A10的表达，碳酸氢钠辅助转运蛋白，负责CSF分泌，因此 CSF在脉络丛处的分泌过多。此外，乙二醇化CSF排水量发布以发挥出色 在新生儿中的作用，由于亚蛛网膜下腔绒毛的分布稀疏，其功能也可能受到损害 遵循GMH。糖基系统涉及星形胶质细胞介导的CSF互化流体（ISF）交换 Virchow-Robin空间，由星形胶质细胞通道蛋白-4驱动。另外，向内整理钾 通道4.1（Kir4.1）与星形胶质细胞中的Aquaporin-4合作，用于调节渗透梯度和 随之而来的水流，但尚未确定其在Glycatic CSF-FISF交换中的作用。星形胶质病 从GMH可能会改变Aquaporin-4和Kir4.1表达或功能，破坏Glychatic CSF-FISM交换 因此减少了CSF的重吸收。我们的总体假设是，遵循GMH，急性铁 超负荷导致诱导SLC4A10和长期脉络丛的CSF过量生产 星形胶质细胞增多会损害正常的CSF通过糖基体系统的重吸收，导致后 新生儿中出血性脑积水。为了检验这一假设，我们将以两个特定的方式进行研究 目标。特定目标1：确定铁诱导的SLC4A10表达在脉络丛中的作用 GMH之后，导致CSF分泌增加。特定目标2：确定GMH诱导的作用 星形胶质细胞增多症和随之而来的Kir4.1和Aquaporin-4在破坏CSF-FISF交换和 CSF通过淋巴结系统清除。

项目成果

Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats.

• DOI: 10.1016/j.bbi.2018.02.015
• 发表时间: 2018-05
• 期刊: Brain, behavior, and immunity
• 作者: Zhang Y;Xu N;Ding Y;Zhang Y;Li Q;Flores J;Haghighiabyaneh M;Doycheva D;Tang J;Zhang JH
• 通讯作者: Zhang JH

Bliverdin reductase-A improves neurological function in a germinal matrix hemorrhage rat model.

• DOI: 10.1016/j.nbd.2017.11.017
• 发表时间: 2018-03
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Zhang Y;Ding Y;Lu T;Zhang Y;Xu N;Yu L;McBride DW;Flores JJ;Tang J;Zhang JH
• 通讯作者: Zhang JH

Activation of GPR40 attenuates neuroinflammation and improves neurological function via PAK4/CREB/KDM6B pathway in an experimental GMH rat model.

• DOI: 10.1186/s12974-021-02209-9
• 发表时间: 2021-07-18
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Xiao J;Cai T;Fang Y;Liu R;Flores JJ;Wang W;Gao L;Liu Y;Lu Q;Tang L;Zhang JH;Lu H;Tang J
• 通讯作者: Tang J

IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model.

• DOI: 10.1155/2021/5913424
• 发表时间: 2021
• 期刊: Oxidative medicine and cellular longevity
• 作者: Liu S;Flores JJ;Li B;Deng S;Zuo G;Peng J;Tang J;Zhang JH
• 通讯作者: Zhang JH

Osteopontin attenuates inflammation via JAK2/STAT1 pathway in hyperglycemic rats after intracerebral hemorrhage.

• DOI: 10.1016/j.neuropharm.2018.06.009
• 发表时间: 2018-08
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Gong L;Manaenko A;Fan R;Huang L;Enkhjargal B;McBride D;Ding Y;Tang J;Xiao X;Zhang JH
• 通讯作者: Zhang JH