Mouse model for inflammation-induced diffuse white matter disease

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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).