Mechanisms of inflammation-associated brain injury: transgenic dissection

描述（由申请人提供）：与早产相关的脑室周围白色物质损伤（PWMI）给患者及其家庭造成严重痛苦，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类型本质上是局灶性的，并被认为是由于过早发育的脑血管破裂、局部缺氧和缺血所致。最终结果是多种细胞类型的坏死性死亡和受影响的白色物质中的囊性积聚。围产期护理的最新进展已导致早产儿的存活率显著提高，局灶性PWMI显著减少。然而，主要影响CNS的髓鞘形成细胞（少突胶质细胞）的弥漫性PWMI的发病率并未降低，并且现在是导致运动和认知障碍的最普遍的PWMI类型，发生在约45-65%的早产儿中。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，在小鼠中模拟了这种日益普遍的PWMI形式。根据表明PWMI与妊娠期和早产儿感染性疾病相关的流行病学数据，我们已经确定，在此脆弱性高峰期给予的单一全身炎症损伤模拟了这种新出现的PWMI形式的许多解剖学和行为学特征。我们建议在这里使用这个新的模型来剖析可能的机制少突胶质细胞损伤和白色物质损失PWMI使用转基因谱系追踪系统标记少突胶质细胞祖细胞和他们的后代，以及条件性基因敲除小鼠中的星形胶质细胞反应被阻断。 公共卫生相关性：脑损伤，包括大脑性麻痹和智力迟钝，与早产有关，给患者及其家庭造成重大痛苦，是社会的主要经济负担。由于流行病学研究表明，这种情况的一个可能的原因是母体感染，我们已经建立了一个小鼠模型，概括疾病，并建议使用该模型来确定母体感染如何导致这些缺陷。拟议的研究预计将揭示新的策略，这些策略将允许开发有助于识别风险婴儿的预测因子和减少患病儿童后果的治疗药物。

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.