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.

摘要 老年性基质出血（GMH）是指在老年性痴呆中， 早产儿的脑电矩阵。出血后脑积水是常见但严重的后果 从GMH。然而，到目前为止还没有有效的治疗方法，只有外科分流术，这会导致巨大的 社会经济负担。因此，为了描述潜在的机制并确定潜在的治疗方法， 目标至关重要。脑脊液主要由脉络丛产生 并被蛛网膜下绒毛重吸收，在新生儿中更大程度上通过胶质淋巴系统重吸收。GMH 导致血液制品的分解、炎症和星形胶质细胞增生，这可以损害脑室周围 组织中负责维持正常CSF流动动力学的组织可能在GMH后受损， 导致出血后脑积水脉络丛专门用于产生CSF， 调节血-脑脊液屏障GMH后溶解红细胞的铁毒性可能导致 slc 4a 10的表达，一种负责CSF分泌的碳酸氢钠协同转运蛋白， 脉络丛脑脊液分泌过多。此外，胶质淋巴CSF引流被假定在脑内的神经元中起着重要作用。 在新生儿中的作用，因为蛛网膜下绒毛分布稀疏，其功能也可能受损 在GMH之后。胶质淋巴系统涉及星形胶质细胞介导的CSF-间质液（ISF）交换， Virchow-Robin空间，其由星形胶质细胞水通道蛋白-4驱动。此外，向内整流钾 通道4.1（Kir4.1）在星形胶质细胞中与水通道蛋白-4协同作用以调节渗透梯度， 尽管其在胶质淋巴CSF-ISF交换中的作用尚未确定。星形胶质细胞增生 可能改变水通道蛋白4和Kir4.1的表达或功能，破坏胶质淋巴CSF-ISF交换 从而减少CSF重吸收。我们的总体假设是，在GMH之后，急性铁 超负荷通过诱导slc 4a 10和长期的 星形胶质细胞增生损害正常CSF通过胶质淋巴系统的重吸收，导致后 出血性脑积水。为了验证这一假设，我们将在两个具体的研究中进行研究。 目标。具体目的1：确定脉络丛中铁诱导的slc 4a 10表达的作用 GMH后，导致CSF分泌增加。具体目标2：确定GMH诱导的 星形胶质细胞增生和随后的Kir4.1和水通道蛋白-4表达破坏CSF-ISF交换， 通过胶质淋巴系统清除CSF。

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

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

脑出血后，骨桥蛋白通过JAK2/STAT1途径通过JAK2/STAT1途径减轻炎症。

• 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

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