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

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