Mechanisms of inflammation-associated brain injury: transgenic dissection

描述（由申请人提供）：与早产相关的心室周围白质损伤（PWMI）给患者及其家人带来了巨大的痛苦，是社会的主要经济负担。需要建立和完善适当的动物模型，以作为了解PWMI发病机制和测试临床前治疗方式的重要工具。历史上，最常见的PWMI类型是局灶性的，被认为是由于过早发育的脑血管破裂，局部缺氧和缺血。最终的结果是多种细胞类型的坏死死亡和病变白质的囊性堆积。围产期护理的最新进展导致了早产儿存活率的显著增加和局灶性PWMI的显著减少。然而，主要影响中枢神经系统髓鞘细胞（少突胶质细胞）的弥漫性PWMI的发病率并没有减少，现在是最普遍的PWMI类型，导致运动和认知障碍，约45-65%的早产儿发生。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，在小鼠中建立了这种日益普遍的PWMI形式的模型。根据流行病学数据显示PWMI与妊娠期和早产儿感染性疾病的关联，我们已经确定，在这一易受伤害的高峰期进行一次系统性炎症性损伤，模仿了这种新出现的PWMI的许多解剖学和行为学特征。我们建议使用这个新模型，利用转基因谱系追踪系统来分析PWMI中少突胶质细胞损伤和白质丢失的可能机制，该系统可以标记少突胶质细胞祖细胞及其后代，以及阻断星形胶质细胞反应的条件敲除小鼠。

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.