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

基本信息

批准号：
8717070
负责人：
STEVEN W LEVISON
金额：
$ 39.08万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/8717070
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 receptor relating to nervous system research study stem subventricular zone transcription factor white matter

项目摘要

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（由适用提供）：围产期脑损伤引起的许多神经系统疾病。尽管没有单一原因这些疾病，但缺氧 - 缺血（H/I）与脑灰质和白质的损害之间存在很强的相关性。尽管在理解缺氧 - 缺血性损伤的发病机理方面取得了进展，但我们对导致永久性脑损伤的机制有不完整的理解，更重要的是，没有明确的解释对再生的失败。研究人员越来越多地开始欣赏这种损伤对脑室下区（SVZ）的影响，即未成熟大脑的区域，它具有赋予产生神经元，星形胶质细胞和寡头胶质细胞的能力的多能神经元干细胞/祖细胞/祖细胞/祖细胞/祖细胞（NSP）。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，并在拮抗特定星形胶质细胞时评估从H/I的恢复。我们的初步数据表明，从围产期H/I恢复后，从SVZ细胞中的星形胶质细胞产生增加，而给以骨髓少突胶质细胞。这是我们的假设是，由于损伤引起的细胞因子的结果，SVZ中神经胶质祖细胞的产生异常，这种神经胶质失调有助于白质寡胶质细胞的永久防御，后者随后发生H/I。关于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在信号有反应。我们假设由于H/I侮辱了现在存在的特定信号，否则就会存在。该提案的具体目的是：1）检验以下假设：围产期H/I增加SVZ中神经胶质祖细胞的星形胶质细胞的产生； 2）检验的假设是，受损的新生儿大脑会产生促进产后SVZ细胞产生星形胶质细胞的因素； 3）确定哪些转录因子通过相关的星形胶质细胞诱导剂在产后SVZ细胞中有效； 4）确定TGF- - 受体ALK5的药物拮抗剂是否会防止在H/I后体外和体内形成异常的星形胶质细胞。我们预计，从这些研究中获得的知识将导致婴儿生存H/I或大脑发育的其他疾病的药物干预，以使婴儿大脑能够更正常地发育。我们从研究中获得的见解也将适用于CNS的广泛损伤和疾病，以及将外源性中性前体移植到大脑中的研究，在该大脑中，过量的星形胶质细分或星形胶质细胞增多被认为是不可能的。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury.

DOI：
10.1159/000477490
发表时间：
2017
期刊：
Developmental neuroscience
影响因子：
2.9
作者：
Kim BH;Guardia Clausi M;Frondelli M;Nnah IC;Saqcena C;Dobrowolski R;Levison SW
通讯作者：
Levison SW