Genetic Mechanisms of Oligodendrogenesis and Remyelination

描述（由申请人提供）：一组不同的成人和儿童CNS疾病，如多发性硬化症和脑室周围白质软化症（脑瘫的主要原因），具有对产生髓鞘的少突胶质细胞损伤的共同特征。我研究的长期目标是了解少突胶质细胞产生和成熟的生物学，以期在白色病变的背景下如何治疗性地增强髓鞘再生。拟议的研究重点是调节出生后啮齿动物大脑中这些过程的分子机制。成年脑室下区（SVZ）最近已被确定为正在进行的少突分化的网站。为了表征参与出生后少突分化的祖细胞群体和遗传因素，我将使用免疫组织化学技术和共聚焦显微镜相结合的方法研究成人SVZ细胞的分子表达谱。我将确定在增殖和表达的SVZ祖细胞在胼胝体局灶性脱髓鞘病变的变化，并与少突胶质细胞的生产，招聘到损伤部位，和髓鞘再生的变化。我以前的工作表明，Dlx同源框转录因子作为胚胎发育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，我将检查Dlx在出生后少突分化的作用，通过产生条件Dlx 2基因敲除小鼠与出生后SVZ祖细胞的Dlx 2功能的损失，以及异位表达Dlx 2使用病毒转导。少突胶质细胞前体（OPCs）的细胞移植已被认为是一种潜在的修复策略，在获得性和先天性髓鞘形成疾病。由于来自Dlx 1&2缺失小鼠的OPCs显示出加速成熟，我将研究这些细胞（与野生型OPCs相比）在先天性脑白质营养不良小鼠模型中的异时移植是否会导致更稳健的髓鞘形成和改善的存活率。总之，该项目将是第一个详细的分析Dlx功能在出生后少突胶质细胞和脱髓鞘损伤的内源性反应，并提供深入了解是否操纵Dlx基因工程细胞可以提高他们的髓鞘形成潜力。敷设总结：常见的小儿和成人神经系统疾病，如脑瘫和多发性硬化，其特征在于由于产生髓鞘的少突胶质细胞的损失或功能障碍而导致的脑白色物质的损伤。本研究项目调查干细胞在成年啮齿动物脑内，可以作为内源性来源的少突胶质细胞，这些细胞在动物模型的白色物质损伤的反应，和细胞移植范例的有效性，以治疗髓鞘形成或脑白质营养不良的先天性疾病。

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.