Chondroitin Sulfate Proteoglycan and Myelination in Intraventricular Hemorrhage

硫酸软骨素蛋白多糖与脑室内出血中的髓鞘形成

• 批准号: 7923921
• 负责人: PRAVEEN BALLABH
• 金额: $ 21.47万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923921
• 关键词: Address; Adult; Affect; Age; Animal Model; Animals; Astrocytes; Autopsy; Axon; Back; Behavioral; Brain; Brain hemorrhage; CSPG3 gene; CSPG4 gene; Cannulas; Cell Death; Cells; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Cerebral cortex; Chondroitin Sulfate Proteoglycan; Chondroitinases; Clinical; Cognitive deficits; Coupled; Data; Diffuse; Dose; Epidermal Growth Factor; Evaluation; Exhibits; Extracellular Matrix; Failure; Gliosis; Glycerol; Goals; Growth Factor; Growth Factor Interaction; Hemorrhage; Hyaluronidase; Immunohistochemistry; Impairment; Infant; Inflammation; Infusion procedures; Inorganic Sulfates; Lead; Lesion; Limb structure; Link; Location; Messenger RNA; Modeling; Molecular; Neonatal Brain Injury; Nervous System Physiology; Newborn Infant; Oligodendroglia; Oryctolagus cuniculus; Peptide Hydrolases; Perinatal; Perinatal subependymal hemorrhage; Pre-Clinical Model; Pregnancy; Premature Infant; Prevention strategy; Process; Prosencephalon; Protein Analysis; Proteoglycan; Pump; Rattus; Reading; Recovery; Regimen; Risk; Role; Saline; Schedule; Silver; Spinal Cord; Staging; Testing; Therapeutic; Time; Transforming Growth Factors; United States; Unspecified or Sulfate Ion Sulfates; Ventricular; Walking; Western Blotting; Writing; base; brevican; decorin; improved; infant brain injury; injured; insight; intraperitoneal; intraventricular hemorrhage; migration; myelination; neonatal hypoxic-ischemic brain injury; nervous system disorder; neurological recovery; novel strategies; oligodendrocyte lineage; phosphacan; postnatal; premature; prevent; public health relevance; pup; versican; white matter; white matter injury

DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) in premature infants predisposes to white matter injury and subsequent cerebral palsy. The most common white matter injury in premature infants is 'gliosis and hypomyelination with intact axons'. In our model of IVH in premature rabbits, there is an arrest of oligodendrocyte (OL) maturation at a pre-myelinating stage. However, the mechanism underlying the maturational arrest of pre-OL and subsequent hypomyelination is unclear. Myelination is a dynamic process that needs an appropriate microenvironment containing growth factors, extracellular matrix molecules and myelinating OL. Chrondroitin sulfate proteoglycans (CSPG)-- neuracan, phosphacan, brevican, decorin, NG2 & versican--are important components of the extracellular matrix (ECM) and are increased in adult and neonatal brain injuries. They are primarily produced by reactive astrocytes and are regulated by transforming growth factor-2 (TGF-2) and epidermal growth factor (EGF). CSPGs have key regulatory functions during migration, proliferation and differentiation of pre-OL. Specifically, degradation of CSPGs by either chondroitinase or protease facilitates migration of OL, loosens the physical barriers in ECM, enhances formation of OL process outgrowths to unsheathe axons and improves interaction of growth factors with OL. Despite this evidence, direct effect(s) of CSPGs on myelination have not been studied. We hypothesize that CSPGs are elevated in premature newborns with IVH and that suppression of CSPG formation will restore myelination of axons and maturation of pre- OL into myelinating OL. Our preliminary data show that expression of CSPGs and growth factors (TGF2 and EGF) are elevated in premature infants and rabbit pups with IVH; and treatment with decorin, a CSPG and natural antagonist of TGF-2, reduces their levels. Our approach is to use a rabbit model that induces IVH with intraperitoneal glycerol. This model results in pups with hemorrhage to exhibit inflammation, cell death and subsequently, lesser myelination and more enhanced gliosis (day 14) compared to controls without IVH. The following specific aims will be addressed: Aim #1. Determine whether the expression of CSPGs (neuracan, phosphacan, brevican, decorin, NG2 & versican) and their regulating growth factors (TGF-2 and EGF) are higher in both premature rabbit pups and infants with IVH compared to controls without IVH. Aim # 2. Determine whether suppression of CSPGs either by chondroitinase or decorin (via TGF-2 inhibition) facilitates maturation of pre-OL, myelination and neurological recovery in premature rabbit pups with IVH. Our study that links CSPGs with failure to myelinate coupled with our novel approaches to regulate CSPG expression may provide effective strategies for prevention of cerebral palsy in infants with IVH. PUBLIC HEALTH RELEVANCE: In the United States, about 12,240 premature infants develop bleeding in and around the ventricle (cavity) of the brain each year, which enhances the risk of white matter injuries and consequent cerebral palsy (weakness in extremities), and cognitive deficits--writing and reading difficulties. In this proposal, we seek to determine the mechanism of brain injuries in these infants with hemorrhage that leads to impairment in walking, reading and writing. In addition, we will test therapeutic strategies that can minimize or prevent cerebral palsy in them. To address these issues, we will use prematurely delivered rabbit pups as an experimental animal and will also use autopsy materials from premature infants with and without brain hemorrhage.

描述（由申请人提供）：早产儿脑室内出血（IVH）易导致白色损伤和随后的脑瘫。早产儿最常见的白色物质损伤是“神经胶质增生和髓鞘形成不足伴轴突完整”。在我们的早产兔IVH模型中，少突胶质细胞（OL）成熟在髓鞘形成前阶段被阻滞。然而，前OL的成熟停滞和随后的髓鞘形成不足的机制尚不清楚。髓鞘形成是一个动态的过程，需要一个适当的微环境，包含生长因子，细胞外基质分子和髓鞘化OL。硫酸软骨素蛋白聚糖（CSPG）-- neuracan、phosphacan、brevican、核心蛋白聚糖、NG 2和多功能蛋白聚糖--是细胞外基质（ECM）的重要组分，并且在成人和新生儿脑损伤中增加。它们主要由反应性星形胶质细胞产生，并受转化生长因子-2（TGF-2）和表皮生长因子（EGF）调节。CSPG在前OL的迁移、增殖和分化过程中具有关键的调节功能。具体而言，通过软骨素酶或蛋白酶降解CSPG促进OL的迁移，放松ECM中的物理屏障，增强OL过程副产物的形成以使轴突脱鞘，并改善生长因子与OL的相互作用。尽管有此证据，但尚未研究CSPG对髓鞘形成的直接影响。我们假设CSPG在患有IVH的早产儿中升高，并且CSPG形成的抑制将恢复轴突的髓鞘形成和前OL成熟为髓鞘形成OL。我们的初步数据表明，早产儿和IVH兔幼崽中CSPG和生长因子（TGF 2和EGF）的表达升高;用CSPG和TGF-2的天然拮抗剂核心蛋白聚糖治疗可降低其水平。我们的方法是使用腹腔内甘油诱导IVH的兔模型。与没有IVH的对照相比，该模型导致具有出血的幼仔表现出炎症、细胞死亡以及随后的较少的髓鞘形成和更多增强的神经胶质增生（第14天）。将讨论以下具体目标：目标1。确定早产兔幼崽和IVH婴儿中CSPG（neuracan、phosphacan、brevican、核心蛋白聚糖、NG 2和versican）及其调节生长因子（TGF-2和EGF）的表达是否高于无IVH的对照组。目标二。确定通过软骨素酶或核心蛋白聚糖（通过TGF-2抑制）抑制CSPG是否有助于患有IVH的早产兔幼仔的前OL成熟、髓鞘形成和神经恢复。我们的研究将CSPG与髓鞘形成失败联系起来，再加上我们调节CSPG表达的新方法，可能为预防IVH婴儿脑瘫提供有效的策略。公共卫生相关性：在美国，每年约有12，240名早产儿发生脑室（腔）内和周围出血，这增加了白色物质损伤和随之而来的脑瘫（四肢无力）以及认知缺陷-书写和阅读困难的风险。在这个建议中，我们试图确定这些出血婴儿的脑损伤机制，导致行走，阅读和写作障碍。此外，我们将测试治疗策略，可以最大限度地减少或预防脑瘫。为了解决这些问题，我们将使用早产的幼兔作为实验动物，还将使用来自有和没有脑出血的早产儿的尸检材料。