ROLE OF EXTRACELLULAR MATRIX IN HYPOXIC-ISCHEMIC PERINATAL WHITE MATTER INJURY

细胞外基质在围产期缺氧缺血性脑白质损伤中的作用

• 批准号: 8173210
• 负责人: Larry S. Sherman
• 金额: $ 5.71万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173210
• 关键词: Acute; Astrocytosis; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Palsy; Cerebrum; Cessation of life; Chronic; Computer Retrieval of Information on Scientific Projects Database; Data; Extracellular Matrix; Funding; Gliosis; Glycosaminoglycans; Grant; Human; Hyaluronan; Hypoxia; Institution; Life; Neurologic; Perinatal; Periventricular white matter injury; Premature Birth; Rattus; Research; Research Personnel; Residual state; Resources; Role; Source; Survivors; Testing; United States National Institutes of Health; disability; fetal infection; myelination; neurovascular unit; novel; premature; prevent; white matter; white matter injury

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. In the premature human brain there is a window of vulnerability when hypoxia-ischemia (H-l), maternal-fetal infection and other insults damage cerebral white matter. We propose to define novel mechanisms in perinatal rat and human by which acute white matter injury leads to disruptions in the neurovascular unit at the level of the extracellular matrix that disrupt normal myelinogenesis. We will test the overall hypothesis that the predilection of the preterm white matter to chronic myelination disturbances after H-l is related to the acute degeneration of preOLs that triggers chronic reactive astrocytosis. Our preliminary data suggest that reactive gliosis leads to the accumulation of the glycosaminoglycan hyaluronan (HA) and that HA can block preOL maturation. We hypothesize that reactive astrocytosis prevents the normal maturation of the residual pool of susceptible preOLs, arrests normal myelination and results in a persistent state of increased vulnerability of the white matter with delayed preOL death through a mechanism that involves HA accumulation.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 人类脑室周围白质损伤（PWMI）是脑损伤的主要形式，也是早产幸存者脑瘫导致终身神经功能障碍的主要原因。当缺氧缺血（H-1）、母胎感染和其他损害脑白质的损伤时，早产儿的大脑存在一个脆弱窗口。我们建议在围产期大鼠和人类中定义新的机制，通过该机制，急性白质损伤导致细胞外基质水平的神经血管单元破坏，从而破坏正常的髓磷脂生成。我们将检验总体假设，即 H-1 后早产白质对慢性髓鞘形成障碍的偏好与触发慢性反应性星形细胞增多症的前 OL 的急性变性有关。我们的初步数据表明，反应性神经胶质增生导致糖胺聚糖透明质酸 (HA) 的积累，并且 HA 可以阻止 preOL 成熟。我们假设反应性星形细胞增多症通过涉及 HA 积累的机制阻止了易受影响的 preOL 残留池的正常成熟，阻止正常髓鞘形成，并导致白质脆弱性增加的持续状态，并延迟 preOL 死亡。