Genetic Mechanisms of Oligodendrogenesis and Remyelination

少突胶质细胞发生和髓鞘再生的遗传机制

基本信息

批准号：
7620085
负责人：
Magdalena A Petryniak
金额：
$ 16.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7620085
关键词：
Accounting Adult Animal Model Area Axon Biology Brain Bromodeoxyuridine Cell Transplantation Cell Transplants Cells Central Nervous System Diseases Cerebral Palsy Cessation of life Child Childhood Chronic Confocal Microscopy Congenital Disorders Corpus Callosum Data Development Disease Effectiveness Embryo Embryonic Development Engraftment Etiology Functional disorder Generations Genes Genetic Goals Homeobox Immunohistochemistry Injury Investigation Knockout Mice Label Lateral Lesion Molecular Molecular Profiling Morbidity - disease rate Multiple Sclerosis Mus Mutation Myelin Nature Neonatal Neuraxis Neurons Oligodendroglia Pathology Periventricular Leukomalacia Population Genetics Process Production Recruitment Activity Research Research Personnel Research Project Grants Rodent Role Site Source Stem cells Techniques Telencephalon Testing Therapeutic Transplantation Viral Work cell type cellular targeting developmental neurobiology genetically modified cells improved in vivo insight leukodystrophy mouse model mouse myelin basic protein myelination nerve stem cell nervous system disorder nestin protein neurogenesis oligodendrocyte precursor postnatal precursor cell progenitor programs repaired response response to injury spinal cord and brain injury subventricular zone transcription factor white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): A diverse group of adult and pediatric CNS disorders, such as multiple sclerosis and periventricular leukomalacia, the leading cause of cerebral palsy, share a common feature of insult to myelin-producing oligodendrocytes. The long-term goal of my research is to understand the biology of oligodendrocyte production and maturation with a view towards how remyelination could be therapeutically enhanced in the setting of white matter pathology. The proposed research focuses on the molecular mechanisms regulating these processes within the postnatal rodent brain. The adult subventricular zone (SVZ) recently has been identified as a site of ongoing oligodendrogenesis. To characterize the progenitor populations and genetic factors involved in postnatal oligodendrogenesis, I will study the molecular expression profile of cells in the adult SVZ using a combination of immunohistochemical techniques and confocal microscopy. I will determine changes in proliferation and expression of SVZ progenitors in response to focal demyelinating lesion in the corpus callosum, and correlate these with changes in oligodendrocyte production, recruitment to the site of injury, and remyelination. My prior work indicates that Dlx homeobox transcription factors act as repressors of oligodendrocyte formation and maturation during embryogenesis. In the proposed project, I will examine the role of Dlx in postnatal oligodendrogenesis by generating conditional Dlx2 knockout mice with loss of Dlx2 function in postnatal SVZ progenitors, as well as ectopically expressing Dlx2 using viral transduction. Cell transplantation of oligodendrocyte precursors (OPCs) has been suggested as a potential repair strategy in both acquired and congenital disorders of myelination. Since OPCs from Dlx1&2 null mice show accelerated maturation, I will investigate whether heterochronic grafting of these cells (versus wild type OPCs) in a mouse model of congenital leukodystrophy leads to more robust myelination and improved survival. In summary, this project will be the first detailed analysis of Dlx function in postnatal oligodendrogenesis and in endogenous responses to demyelinating injury, and offer insight into whether manipulation of Dlx in genetically engineered cells could enhance their myelinating potential. Lay Summary: Common pediatric and adult neurological disorders, such as cerebral palsy and multiple sclerosis, are characterized by damage to the brain's white matter due to loss or dysfunction of myelin producing oligodendrocytes. This research project investigates stem cells within the adult rodent brain that could serve as endogenous sources of oligodendrocytes, the response of these cells in animal models of white matter injury, and the effectiveness of cell-transplantation paradigms to treat a congenital disorder of myelin formation or leukodystrophy.

描述（由申请人提供）：多样化的成年和小儿中枢神经系统疾病，例如多发性硬化症和脑室白细胞菌，这是大脑麻痹的主要原因，具有侮辱性髓鞘产生的产生髓磷脂的共同特征。我的研究的长期目标是了解少突胶质细胞生产和成熟的生物学，以期在白质病理学的环境中如何治疗性地进行治疗。拟议的研究重点是调节产后啮齿动物大脑中这些过程的分子机制。最近，成年室内室内区（SVZ）被确定为正在进行的寡构成部位。为了表征产后寡头生成的祖细胞和遗传因素，我将使用免疫组织化学技术和共聚焦显微镜的组合研究成人SVZ中细胞中细胞的分子表达谱。我将确定SVZ祖细胞增殖和表达的变化，响应于call体的局灶性脱髓鞘病变，并将其与少突胶质细胞产生，募集到损伤部位和Remyelination的变化相关。我先前的工作表明，DLX同源型转录因子是胚胎发生过程中少突胶质细胞形成和成熟的阻遏物。在拟议的项目中，我将通过产生有条件的DLX2基因敲除小鼠在产后SVZ祖细胞中丧失DLX2功能，并在异位使用病毒转导表达DLX2，从而检查DLX在产后寡聚的作用中的作用。少突胶质细胞前体（OPC）的细胞移植被认为是髓鞘化和先天性疾病的潜在修复策略。由于来自DLX1和2空小鼠的OPC表现出加速成熟，因此我将研究这些细胞（与野生型OPC）在先天性白细胞育肥的小鼠模型中是否会导致更强大的髓鞘形成和提高生存率。总而言之，该项目将是对出生后寡导体发生的DLX功能以及对脱髓鞘损伤的内源性反应的首次详细分析，并可以深入了解遗传工程细胞中DLX是否可以增强其髓鞘的潜力。摘要摘要：常见的儿科和成人神经系统疾病（例如脑瘫和多发性硬化症）的特征是由于髓磷脂产生少突胶质细胞的损失或功能障碍而损害大脑的白质。该研究项目调查了成年啮齿动物大脑中的干细胞，这些干细胞可以用作少突胶质细胞的内源性来源，这些细胞在白质损伤的动物模型中的反应以及细胞移植范式治疗髓磷脂形成或白血病的先天性疾病的有效性。