Glial Dysgenesis in the Injured Developing Brain

描述（由申请人提供）：围产期脑损伤导致许多神经系统疾病。虽然这些疾病没有单一的原因，但缺氧缺血（H/I）与大脑灰质和白质损伤之间存在很强的相关性。尽管对缺氧缺血性损伤的发病机制的了解有所进展，但我们对导致永久性脑损伤的机制还不完全了解，更重要的是，对再生失败还没有明确的解释。越来越多的研究人员开始意识到这种损伤对心室下区（SVZ）的影响，SVZ是未成熟大脑的一个区域，其中包含具有生成神经元、星形胶质细胞和少突胶质细胞能力的多潜能神经干细胞/祖细胞（NSPs）。该建议的具体目标是确定诱导胶质前体向星形胶质细胞分化的信号，并评估特定星形胶质细胞诱导剂拮抗后H/I的恢复情况。我们的初步数据表明，在围产期H/I恢复后，SVZ细胞以髓鞘少突胶质细胞为代价增加星形胶质细胞的产生。因此，我们的假设是，由于损伤诱导的细胞因子，SVZ的胶质祖细胞产生了异常的星形胶质细胞，这种胶质细胞的发育不良导致了H/I后白质少突胶质细胞的永久性缺陷。对大脑发育的开创性研究表明，神经前体对控制其分化选择的外部信号有反应。我们假设，作为H/I侮辱的结果，特定的信号现在出现了，否则将不存在。本研究的具体目的是：1)验证围产期H/I增加SVZ神经胶质祖细胞生成星形细胞的假设；2)验证受损新生儿脑产生促进出生后SVZ细胞生成星形胶质细胞因子的假说；3)通过相关星形胶质诱导剂确定哪些转录因子在出生后SVZ细胞中具有活性；4)确定TGF-¿受体ALK5的药理拮抗剂是否能阻止H/I后体外和体内星形胶质细胞的异常生成。我们预计，从这些研究中获得的知识将导致对H/I或其他大脑发育障碍婴儿的药物干预，使婴儿大脑发育更正常。我们从研究中获得的见解也将适用于广泛的中枢神经系统损伤和疾病，以及将外源性神经前体移植到大脑中的研究，在这些研究中，过度的星形胶质细胞分化或星形胶质细胞增生被认为是不可取的。

DESCRIPTION (provided by applicant): There are a number of neurological disorders that result from perinatal brain damage. While there is no single cause of these disorders, there is a strong correlation between hypoxia-ischemia (H/I) and damage to the cerebral gray and white matter. Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, we have an incomplete appreciation for the mechanisms leading to permanent brain injury and more importantly there is no clear explanation for the failure of regeneration. Increasingly, investigators are beginning to appreciate the impact of this injury on the subventricular zone (SVZ), which is that region of the immature brain that harbors the multipotential neural stem cells/progenitors (NSPs) that are endowed with the ability to generate neurons, astrocytes and oligodendrocytes. The specific goal of this proposal is to identify signals that induce the differentiation of glial precursors towards astrocytes and to evaluate recovery from H/I when specific astrocyte inducers are antagonized. Our preliminary data indicate that there is an increase in the production of astrocytes from SVZ cells at the expense of myelinating oligodendrocytes following recovery from perinatal H/I. Thus, our hypothesis is that as a result of injury-induced cytokines, that there is aberrant production of astrocytes from glial progenitors in the SVZ and that this glial dysgnesis contributes to the permanent deficit in white matter oligodendrocytes that occurs subsequent to H/I. Seminal studies on brain development have shown that neural precursors are responsive to extrinsic signals that govern their differentiation choices. We hypothesize that as a result of an H/I insult that specific signals are now present that would otherwise be absent. The specific aims of this proposal are to: 1) Test the hypothesis that perinatal H/I increases the production of astrocytes from glial progenitors in the SVZ; 2) Test the hypothesis that the damaged neonatal brain produces factors that promote astrocyte generatation from postnatal SVZ cells; 3) Establish which transcription factors are active in postnatal SVZ cells by relevant astroglial inducers; and 4) Establish whether a pharmacological antagonist of the TGF-¿ receptor, ALK5, will prevent the aberrant production of astrocytes in vitro and in vivo after H/I. We anticipate that the knowledge obtained from these studies will lead to pharmacological interventions for infants surviving H/I or other disturbances of brain development to enable the infant brain to develop more normally. The insights we gain from our studies also will be applicable to a broad range of injuries and diseases of the CNS, as well as to studies where exogenous neural precursors will be transplanted into the brain, where excessive astroglial differentiation or astrogliosis are deemed undesirable. PUBLIC HEALTH RELEVANCE: Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, we have an incomplete appreciation for the mechanisms leading to permanent brain injury and more importantly there is no clear explanation for the failure of regeneration. The specific goal of this proposal is to identify signals that induce the differentiation of neural precursors towards astrocytes and to evaluate recovery from H/I when specific astrocyte inducers are antagonized. The insights we gain from our studies also will be applicable to a broad range of injuries and diseases of the CNS, as well as to studies where exogenous neural precursors will be transplanted into the brain, where excessive astroglial differentiation or astrogliosis are deemed undesirable.