Mechanisms of inflammation-associated brain injury: transgenic dissection

炎症相关脑损伤的机制：转基因解剖

• 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
• 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

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）：与早产相关的脑室周围白质损伤（PWMI）给患者及其家人带来巨大痛苦，并且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。从历史上看，最常见的 PWMI 类型本质上是局灶性的，被认为是由于过早发育的脑血管破裂、局部缺氧和缺血造成的。最终结果是多种细胞类型坏死性死亡，并在受影响的白质中出现囊性积累。围产期护理的最新进展显着提高了早产儿的存活率，并显着降低了局灶性 PWMI。然而，主要影响中枢神经系统髓鞘形成细胞（少突胶质细胞）的弥漫性 PWMI 的发病率并未减少，目前是最常见的 PWMI 类型，导致运动和认知障碍，约 45-65% 的早产儿发生这种情况。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。根据流行病学数据表明 PWMI 与妊娠期和早产儿期间的传染病之间的关联，我们确定，在这个脆弱性高峰期进行的单一全身性炎症损伤模仿了这种新出现的 PWMI 形式的许多解剖和行为特征。我们在这里建议使用这种新模型来剖析 PWMI 中少突胶质细胞损伤和白质损失的可能机制，使用标记少突胶质细胞祖细胞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，也是社会的重大经济负担。由于流行病学研究表明，这种情况的可能原因是母体感染，因此我们建立了一个重现该疾病的小鼠模型，并建议使用该模型来确定母体感染如何导致这些缺陷。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高危婴儿的预测因子和减少患病儿童后果的治疗药物。