Mouse model for inflammation-induced diffuse white matter disease

炎症诱导的弥漫性白质疾病的小鼠模型

• 批准号: 7662540
• 负责人: JAMES A WASCHEK
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662540
• 关键词: Adenylate Cyclase; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Blood Vessels; Brain; Brain Hypoxia-Ischemia; Cells; Cerebral Palsy; Cessation of life; Communicable Diseases; Data; Development; Diffuse; Disease; Epidemiology; Family; Future; Human; Incidence; Indium; Inflammation; Inflammatory; Injury; Light; Mental Retardation; Modality; Modeling; Molecular; Nature; Necrosis; Neonatal; Neurologic; Neuropeptides; Oligodendroglia; Pathogenesis; Peptides; Perinatal; Perinatal Care; Periventricular white matter injury; Pituitary Gland; Pregnancy; Premature Birth; Premature Infant; Protocols documentation; Research Personnel; Role; Rupture; Societies; Staging; Survivors; Testing; Time; Vasoactive Intestinal Peptide; White Matter Disease; cell type; design; disability; improved; in vivo; mouse model; neuroinflammation; oligodendrocyte precursor; progenitor; white matter

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).

描述（由申请人提供）：脑室周围白色物质损伤（PWMI）是与早产相关的脑瘫的主要原因，对患者及其家庭造成重大痛苦，并且是社会的主要经济负担。 动物模型的建立对于了解PWMI的发病机制和研究新的治疗方法至关重要。 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。 最终的结果是坏死性死亡和所有类型的细胞在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，并且现在是导致智力迟钝的最普遍的PWMI类型。 研究人员建议建立一种新的PWMI小鼠模型，在该模型中，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PWMI与妊娠期感染性疾病相关，因此他们将确定炎症损伤是否足以诱导PWMI，如果是，则涉及潜在机制。 在未来的应用中，他们预计使用该模型来研究两种具有强效体内抗炎作用的神经肽VIP和PACAP（分别为血管活性肠肽和垂体腺苷酸环化酶激活肽）的保护作用。