The role of VEGF in neonatal rat brain after perinatal hypoxic-ischemic damage

描述（由申请人提供）：围产期缺氧缺血（H/I）与脑瘫和儿童广泛的其他神经功能缺损密切相关。虽然一些研究人员将注意力集中在使用外源性干细胞进行修复上，但我们的实验室正在评估室下区（SVZ）的常驻前体的再生潜力。修复受损器官所需的两个关键过程是增加前体细胞的数量，并将其分化为需要替换的细胞类型。我们最近的初步数据表明：1）虽然SVZ在H/I损伤后尺寸扩大，但星形胶质细胞和少突胶质细胞的产生发生了变化; 2）血管内皮生长因子（VEGF），缺血后组织修复的关键介质，在H/I后被快速诱导;和3）VEGF在体外增加从双能胶质祖细胞的星形胶质细胞的特化。虽然已经在成人中风模型中研究了VEGF，但还没有已知的研究检查围产期脑损伤后的VEGF蛋白。我们的假设是VEGF同种型导致SVZ祖细胞增殖和分化向星形胶质细胞表型而不是H/I损伤后更合适的少突胶质细胞谱系的异常转变。具体目的1：在围产期H/I后，表征SVZ中VEGF A、B和C以及两种主要受体Flt-1和Flk-1的空间和时间表达谱。具体目标二：体外H/I后，检测外源性VEGF-A对SVZ源性双能胶质祖细胞增殖和分化的影响。所有实验将使用已建立的H/I动物模型在大鼠幼仔中进行。重要的是，这些翻译研究调查了临床上重要的人类疾病。这个项目将提高我们对新生儿脑损伤后干细胞增殖和分化的理解。 这些研究将阐明VEGF在围产期脑损伤背景下对神经前体细胞增殖和分化的作用。公共卫生相关性：儿童和婴儿的脑损伤是一个严重的公共卫生问题，会导致长期的认知、运动和情感障碍。这项研究的目的是更好地了解H/L后大脑如何自我修复。我们的工作也将与其他中枢神经系统损伤和疾病有关，如中风和创伤性脑损伤，其中干细胞疗法将被实施。

DESCRIPTION (provided by applicant): Perinatal hypoxia-ischemia (H/l) is strongly associated with cerebral palsy and a wide spectrum of other neurological deficits in children. While some researchers focus their attention on the use of exogenous stem cells for repair, our lab is evaluating the regenerative potential of the resident precursors of the subventricular zone (SVZ). Two key processes required to repair damaged organs are to amplify the number of precursors and to direct their differentiation towards the cell types that need to be replaced. Our most recent preliminary data indicate: 1) although the SVZ expands in size after H/l injury, there is a shift in the production of astrocytes and oligodendrocytes; 2) vascular endothelial growth factor (VEGF), a key mediator of tissue repair after ischemia, is rapidly induced after H/l; and 3) VEGF increases the specification of astrocytes from bipotential glial progenitors in vitro. While VEGF has been studied in adult stroke models, there are no known studies examining VEGF proteins after perinatal brain damage. Our hypothesis is that VEGF isoforms cause an aberrant shift in the proliferation and differentiation of SVZ progenitors towards astrocytic phenotypes instead of a more appropriate oligodendrocyte lineage after H/l injury. The following specific aims are proposed to test these hypotheses: Specific Aim 1: To characterize the expression profiles spatially and temporally in the SVZ of VEGFs A, B and C and the two main receptors, Flt-1 and Flk-1 after perinatal H/l. Specific Aim 2: To determine the effect of exogenous VEGF-A after in vitro H/l on the proliferation and differentiation of SVZ-derived bipotential glial progenitors. All experiments will be performed on rat pups using an established animal model for H/l. Importantly, these translational studies investigate a clinically important human condition. This project will enhance our understanding of stem cell proliferation and differentiation in the neonatal brain after injury. These studies will elucidate the role of VEGF on neural progenitor cell proliferation and differentiation in the context of perinatal brain injury. PUBLIC HEALTH RELEVANCE: Brain injury in children and infants is a serious public health issue that results in long term cognitive, motor and emotional handicaps. The goal of this research is to better understand how the brain repairs itself after H/l. Our work will also be relevant to other injuries and diseases of the CNS, such as stroke and traumatic brain injury where stem cell therapies will be implemented.