Mechanisms of inflammation-associated brain injury: transgenic dissection

炎症相关脑损伤的机制：转基因解剖

基本信息

批准号：
7917975
负责人：
JAMES A WASCHEK
金额：
$ 22.54万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-19 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917975
关键词：
Acceleration Affect Animal Model Apoptosis Area Behavioral Blood Vessels Brain Brain Hypoxia-Ischemia Brain Injuries Cells Cerebral Palsy Cessation of life Child Cognitive Communicable Diseases Data Defect Development Diffuse Disease Dissection Epidemiologic Studies Epidemiology Family Human Incidence Indium Infant Infection Inflammation Inflammatory Injection of therapeutic agent Injury Knock-out Knockout Mice Label Light Lipopolysaccharides Mediating Mental Retardation Methods Modality Modeling Molecular Target Motor Mus Natural regeneration Nature Necrosis Neonatal Neurologic Oligodendroglia Pathogenesis Perinatal Perinatal Care Peripheral Periventricular white matter injury Population Preclinical Testing Pregnancy Premature Birth Premature Infant Process Risk Rupture Societies Staging Subcutaneous Injections Survivors System Term Birth Testing Therapeutic Agents Therapeutic Intervention Time Transgenic Mice Transgenic Organisms astrogliosis cell type disability improved mouse model myelination neuroinflammation oligodendrocyte precursor postnatal progenitor promoter public health relevance pup response tool white matter white matter damage white matter injury

项目摘要

DESCRIPTION (provided by applicant): Periventricular white matter injury (PWMI) associated with premature birth results in significant suffering to the afflicted and their families and is a major financial burden to society. Appropriate animal models need to be established and refined to serve important tools to understanding the pathogenesis of PWMI and for testing preclinical treatment modalities. Historically, the most prevalent type of PWMI was focal in nature, and thought to be due to rupture of prematurely developed brain blood vessels, local hypoxia and ischemia. The final result was necrotic death of multiple cell types and cystic accumulation in the affected white matter. Recent advances in perinatal care have led to a dramatically increased survival of preterm infants and a significant reduction in focal PWMI. However, the incidence of a diffuse form of PWMI, primarily affecting the myelinating cells of the CNS (oligodendrocytes), has not decreased, and is now the most prevalent type of PWMI leading to motor and cognitive disabilities, occurring in about 45-65% of pre-term births. We have modeled this increasingly- prevalent form of PWMI in mice by inducing injury at a developmental time point at which oligodendrocyte progenitors are most vulnerable. In light of epidemiological data which indicate an association of PWMI with infectious diseases during pregnancy and preterm infants, we have determined that a single systemic inflammatory insult administered at this time of peak vulnerability mimics many of the anatomical and behavioral features of this newly-emerging form of PWMI. We propose here to use this new model to dissect the possible mechanisms of oligodendrocyte damage and white matter loss in PWMI using a transgenic lineage tracing system which labels oligodendrocyte progenitors and their progeny, as well as a conditional knockout mouse in which the astrogliotic response is blocked. PUBLIC HEALTH RELEVANCE: Brain injury, including cerebral palsy and mental retardation is associated with premature birth and results in significant suffering to the afflicted and their families and is a major financial burden to society. As epidemiological studies indicate that a likely cause for this condition is maternal infection, we have established a mouse model which recapitulates the disease, and propose to use the model to determine how maternal infection leads to these defects. The proposed studies are expected to reveal new strategies that will allow the development of both predictors that help identify infants at risk and therapeutic agents reduce the consequences in afflicted children.

描述（由申请人提供）：与早产相关的脑室白质损伤（PWMI）导致对痛苦的人及其家人产生重大苦难，并且是社会的主要财务负担。需要建立适当的动物模型并精制，以提供重要的工具，以了解PWMI的发病机理和测试临床前治疗方式。从历史上看，最普遍的PWMI类型在本质上是焦点，被认为是由于过早发育的脑血管，局部缺氧和缺血的破裂所致。最终结果是多种细胞类型的坏死死亡和受影响的白质中的囊性积累。围产期护理的最新进展导致早产儿的存活率急剧增加，局灶性PWMI显着下降。然而，PWMI的弥漫形式的发生率主要影响CNS的髓细胞（少突胶质细胞）的发生率尚未降低，现在是导致运动和认知障碍的最普遍类型的PWMI，发生在前期出生的45-65％中。我们通过在少突胶质细胞祖细胞最脆弱的发育时间点诱导损伤来模拟小鼠中普遍存在的PWMI形式。鉴于流行病学数据表明PWMI在怀孕期间与传染病与传染病的关联，我们已经确定，在峰值脆弱性的这一时，单一的全身性炎症性侵入模仿了PWMI的这种新形式的许多解剖学和行为特征。我们在这里建议使用这种新模型来剖定PWMI中少突胶质细胞损伤和白质损失的可能机制，使用转基因谱系跟踪系统标记少突胶质细胞祖细胞及其后代，以及其条件敲除小鼠，而在该系统中，Atrogliotic响应被阻塞。公共卫生相关性：包括脑瘫和智力低下在内的脑损伤与早产有关，并给受伤人群及其家人带来重大痛苦，这是对社会的重大财务负担。由于流行病学研究表明，这种情况的可能原因是母体感染，我们已经建立了一种概括疾病的小鼠模型，并建议使用该模型来确定孕产妇感染如何导致这些缺陷。预计拟议的研究将揭示新的策略，这些策略将允许发展这两个预测因子，以帮助识别有风险的婴儿和治疗剂减少受伤儿童的后果。