Glial Dysgenesis in the Injured Developing Brain

受伤发育中的大脑中的神经胶质发育不全

• 批准号: 8442313
• 负责人: STEVEN W LEVISON
• 金额: --
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442313
• 关键词: Animals; Astrocytes; Axon; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Bromodeoxyuridine; Candidate Disease Gene; Cell Lineage; Cell Proliferation; Cells; Central Nervous System Diseases; Cerebrum; Data; Development; Disease; EGF gene; EP300 gene; Environment; Enzyme-Linked Immunosorbent Assay; Failure; Generations; Glial Differentiation; Glial Fibrillary Acidic Protein; Goals; Hypoxia; Immunofluorescence Immunologic; Immunohistochemistry; In Situ Hybridization; In Vitro; Infant; Injury; Intervention; Knowledge; LIF gene; Label; Lead; Ligands; Messenger RNA; Morbidity - disease rate; Natural regeneration; Neonatal; Neurons; Oligodendroglia; Pathogenesis; Perinatal; Perinatal Brain Injury; Perinatal Hypoxia; Phosphorylation; Play; Production; Proteins; Rattus; Recovery; Research; Research Personnel; Role; Seminal; Signal Transduction; Signaling Molecule; Specific qualifier value; Stem cells; TGF-beta type I receptor; Testing; Transcription Factor 3; Transplantation; astrogliosis; central nervous system injury; combinatorial; cytokine; gliogenesis; gray matter; in vivo; injured; insight; myelination; neonatal hypoxic-ischemic brain injury; nerve stem cell; nervous system disorder; novel therapeutics; postnatal; prevent; progenitor; programs; promoter; public health relevance; receptor; relating to nervous system; research study; stem; subventricular zone; transcription factor; white matter

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.

描述（由申请人提供）：有许多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原因，但缺氧缺血（H/I）与脑损伤之间存在很强的相关性。尽管在了解缺氧缺血性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还没有完全了解，更重要的是，对于再生失败还没有明确的解释。研究人员开始认识到这种损伤对脑室下区 (SVZ) 的影响，该区域是未成熟大脑中蕴藏着多能神经干细胞/祖细胞 (NSP) 的区域，这些细胞被赋予了生成神经元、星形胶质细胞和神经元的能力。该提案的具体目标是识别诱导神经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被拮抗时从 H/I 中恢复的情况。我们的初步数据表明，从围产期 H/I 恢复后，SVZ 细胞星形胶质细胞的产生增加，但髓鞘化少突胶质细胞的数量增加。因此，我们的假设是，由于损伤诱导的细胞因子，存在异常。 SVZ 中的神经胶质祖细胞产生星形胶质细胞，这种神经胶质发育障碍导致 H/I 后白质少突胶质细胞的永久性缺陷。关于大脑发育的研究表明，神经前体对控制其分化选择的外在信号做出反应，我们认为，由于 H/I 损伤，现在出现了原本不存在的特定信号。目的是： 1) 检验围产期 H/I 增加 SVZ 神经胶质祖细胞生成星形胶质细胞的假设；2) 检验受损新生儿大脑产生促进出生后星形胶质细胞生成的因子的假设； SVZ 细胞；3) 确定哪些转录因子在相关星形胶质细胞诱导剂的作用下在出生后 SVZ 细胞中具有活性；4) 确定 TGF-¿受体 ALK5 将在 H/I 后在体外和体内防止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幸存的 H/I 或其他大脑发育障碍的婴儿进行药物干预，从而使 H/I 存活下来。我们从研究中获得的见解也将适用于中枢神经系统的广泛损伤和疾病，以及将外源神经前体移植到大脑中的研究，其中星形胶质细胞过度分化。或者星形胶质细胞增生症被认为是不受欢迎的。