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: 8066317
• 负责人: STEVEN W LEVISON
• 金额: $ 25.63万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066317
• 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. 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.

描述（由申请人提供）：有一些神经系统疾病，导致围产期脑损伤。虽然这些疾病没有单一的原因，但缺氧缺血（H/I）与大脑灰质和白色物质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不完全了解，更重要的是对再生失败没有明确的解释。越来越多的研究人员开始认识到这种损伤对脑室下区（SVZ）的影响，SVZ是未成熟大脑的一个区域，该区域含有多能神经干细胞/祖细胞（NSP），这些神经干细胞/祖细胞具有产生神经元，星形胶质细胞和少突胶质细胞的能力。该提案的具体目标是确定诱导神经胶质前体向星形胶质细胞分化的信号，并评估当特定星形胶质细胞诱导剂被拮抗时从H/I恢复。我们的初步数据表明，在从围产期H/I恢复后，SVZ细胞产生的星形胶质细胞增加，而髓鞘形成的少突胶质细胞减少。因此，我们的假设是，作为损伤诱导的细胞因子的结果，SVZ中的胶质祖细胞异常产生星形胶质细胞，并且这种胶质细胞发育不良导致H/I后发生的白色少突胶质细胞的永久性缺陷。对大脑发育的研究表明，神经前体对支配其分化选择的外部信号有反应。我们假设，作为H/I损伤的结果，现在存在否则将不存在的特定信号。本研究的具体目的是：1）检验围产期H/I增加SVZ中胶质祖细胞产生星形胶质细胞的假设; 2）检验损伤的新生儿脑产生促进出生后SVZ细胞产生星形胶质细胞的因子的假设; 3）确定哪些转录因子通过相关的星形胶质细胞诱导剂在出生后SVZ细胞中有活性;以及4）确定TGF-β受体的药理学拮抗剂ALK 5是否会在体外和体内防止H/I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H/I或其他脑发育障碍存活的婴儿进行药物干预，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CNS损伤和疾病，以及将外源性神经前体移植到大脑中的研究，其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。 公共卫生相关性：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不完全了解，更重要的是对再生失败没有明确的解释。该提案的具体目标是确定诱导神经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的恢复。我们从研究中获得的见解也将适用于广泛的CNS损伤和疾病，以及将外源性神经前体移植到大脑中的研究，其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。