Mouse model for inflammation-induced diffuse white matter disease

描述（由申请人提供）：脑室周围白质损伤（PWMI）是与早产相关的脑瘫的主要原因，给患者及其家人带来了巨大的痛苦，也是社会的主要经济负担。动物模型的建立对于了解PWMI的发病机制和探索新的治疗方式至关重要。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。最终的结果是坏死死亡和所有类型的细胞在受影响的白质囊性堆积。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，现在是导致智力迟钝的最常见的PWMI类型。在此，研究者建议建立一种新的小鼠PWMI模型，在OL祖细胞最脆弱的发育时间点诱导损伤。由于流行病学数据表明妊娠期PWMI与传染病有关，因此他们将确定炎症性损伤是否足以诱发PWMI，如果是的话，可能涉及的机制。在未来的应用中，他们期望利用该模型研究两种具有有效体内抗炎作用的神经肽的保护作用，VIP和PACAP（分别是血管活性肠肽和垂体腺苷酸环化酶激活肽）。

DESCRIPTION (provided by applicant): Periventricular white matter injury (PWMI), a major cause of cerebral palsy associated with premature birth, results in significant suffering to the afflicted and their families, and is a major financial burden to society. The establishment of animal models is critical to understanding the pathogenesis of PWMI and for examining new 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 and cystic accumulation of all cell types 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 mental retardation. The investigators propose here to establish a new mouse model of PWMI in which injury is induced at a developmental time point at which OL progenitors are most vulnerable. Because epidemiological data indicate an association of PWMI with infectious diseases in pregnancy, they will determine if an inflammatory insult is sufficient to induce PWMI, and if so, the potential mechanisms involved. Among future applications, they anticipate using the model to study the protective roles of two neuropeptides with potent in vivo anti-inflammatory actions, VIP and PACAP (vasoactive intestinal peptide and pituitary adenylyl cyclase activating peptide, respectively).