Mechanisms of inflammation-associated brain injury: transgenic dissection

描述(申请人提供)：与早产相关的脑室周围白质损伤(PWMI)会给患者及其家人带来巨大的痛苦，是社会的主要经济负担。需要建立和改进合适的动物模型，以便为了解PWMI的发病机制和测试临床前治疗方式提供重要工具。从历史上看，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质中的囊性堆积。围产期护理的最新进展大大提高了早产儿的存活率，显着减少了局限性PWMI。然而，弥漫性PWMI的发生率并没有下降，主要影响到CNS(少突胶质细胞)的髓鞘细胞，现在是导致运动和认知障碍的最常见的PWMI类型，大约45%-65%的早产儿发生。我们在小鼠中模拟了这种日益流行的PWMI形式，方法是在少突胶质前体细胞最脆弱的发育时间点诱导损伤。根据流行病学数据表明PWMI与妊娠和早产儿的传染病有关，我们已经确定，在脆弱程度达到顶峰时给予单一的全身炎性侮辱，就能模拟这种新出现的PWMI的许多解剖和行为特征。我们建议使用这个新的模型来分析PWMI中少突胶质细胞损伤和白质丢失的可能机制，使用标记少突胶质细胞前体及其后代的转基因谱系追踪系统，以及星形胶质细胞反应被阻断的条件性基因敲除小鼠。 公共卫生相关性：脑损伤，包括脑瘫和智力低下，与早产有关，给患者及其家人带来巨大痛苦，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原因是母体感染，我们建立了一个重述这种疾病的小鼠模型，并建议使用该模型来确定母体感染如何导致这些缺陷。预计拟议的研究将揭示新的策略，允许开发有助于识别处于危险中的婴儿的预测因素和减少受影响儿童的后果的治疗剂。

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.