Glial Dysgenesis in the Injured Developing Brain

描述(申请人提供)：有一些神经系统疾病是由围产期脑损伤引起的。虽然这些疾病没有单一的原因，但缺氧/缺血(H/I)与大脑灰质和白质的损害有很强的相关性。尽管对缺氧缺血性脑损伤的发病机制研究取得了进展，但我们对导致永久性脑损伤的机制认识还不完全，更重要的是，对于再生失败的原因还没有明确的解释。越来越多的研究人员开始意识到这种损伤对脑室下区(SVZ)的影响，SVZ是未成熟大脑中含有多潜能神经干细胞/祖细胞(NSP)的区域，NSP被赋予生成神经元、星形胶质细胞和少突胶质细胞的能力。该方案的具体目标是确定诱导胶质前体细胞向星形胶质细胞分化的信号，并评估当特定的星形胶质细胞诱导剂被拮抗时，从缺氧/缺血中恢复的情况。我们的初步数据表明，在围产期H/I恢复后，SVZ细胞产生的星形胶质细胞增加，但髓鞘少突胶质细胞减少。因此，我们的假设是，由于损伤诱导的细胞因子，SVZ内神经胶质前体细胞产生星形胶质细胞的异常，这种胶质细胞发育障碍导致缺氧后脑白质少突胶质细胞的永久性缺陷。脑发育的开创性研究表明，神经前体细胞对控制其分化选择的外部信号做出反应。我们假设，作为H/I侮辱的结果，现在出现了原本不存在的特定信号。这一建议的具体目的是：1)验证围生期H/I增加SVZ内神经胶质前体细胞产生星形胶质细胞的假设；2)检验损伤的新生儿大脑产生促进出生后SVZ细胞生成星形胶质细胞的因子的假设；3)确定哪些转录因子在出生后SVZ细胞中通过相关的星形胶质细胞诱导剂激活；以及4)确定转化生长因子受体的药理拮抗剂Alk5能否在体外和体内阻止缺氧缺血后星形胶质细胞的异常产生。我们预计，从这些研究中获得的知识将导致对存活于缺氧/缺血或其他脑发育障碍的婴儿进行药物干预，使婴儿的大脑发育更正常。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多症被认为是不可取的。 公共卫生相关性：尽管在了解缺氧缺血损伤的发病机制方面取得了进展，但我们对导致永久性脑损伤的机制尚不完全了解，更重要的是，对于再生失败的原因还没有明确的解释。该方案的具体目标是识别诱导神经前体向星形胶质细胞分化的信号，并评估当特定的星形胶质细胞诱导剂被拮抗时，从缺氧/缺血中恢复的情况。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多症被认为是不可取的。

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.