Inflammation and NG2 Cell Differentiation

炎症和 NG2 细胞分化

基本信息

批准号：
8277186
负责人：
Akiko Nishiyama
金额：
$ 32.85万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277186
关键词：
Active Immunization Adult Affect BHLH Protein Bacterial Artificial Chromosomes Brain CSPG4 gene Cell Count Cell Differentiation process Cell Proliferation Cells Characteristics Chronic Complex Demyelinating Diseases Demyelinations Development DsRed Erinaceidae Experimental Autoimmune Encephalomyelitis Failure Family Genes Genetic Genetic Transcription Histone H3 Histones Human Infiltration Inflammation Inflammatory Knockout Mice Lesion Ligands Lysine Maps Methyltransferase Mitogen-Activated Protein Kinases Modeling Modification Multiple Sclerosis Multiple Sclerosis Lesions Mus NG2 antigen Neuraxis Neuroglia Neurologic Oligodendroglia Outcome Study PDGFRB gene Pathology Pathway interactions Peptides Phase Platelet-Derived Growth Factor alpha Receptor Play Polycomb Reporter Rodent Model Role Signal Transduction Spinal Cord Spinal cord injury Stem cells Tamoxifen Techniques Testing Transgenic Mice United States astrogliosis base bone morphogenic protein clinical effect clinically relevant design embryonic stem cell gray matter high throughput screening in vivo member myelination notch protein novel therapeutics oligodendrocyte lineage oligodendrocyte-myelin glycoprotein overexpression promoter recombinase remyelination repaired tool transcription factor white matter

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a demyelinating disease that affects 350,000 people in the U.S. and is a major cause of chronic neurological deficit, affecting adults during their most active period of their lives. Remyelination failure is a characteristic of long-standing and primary progressive lesions of MS and is associated with impulse conduction failure and axonal pathology. Despite the debilitating clinical effects of remyelination failure, the reason why some lesions are effectively remyelinated while others are not remains unclear. Glial cells that express the NG2 proteoglycan (NG2 cells) exist widely throughout the mature central nervous system. Recent genetic fate mapping studies have provided direct demonstration that they generate oligodendrocytes not only during development but also in the mature central nervous system. Using new transgenic mouse lines that we have generated, we have observed that deletion of the basic helix-loop-helix transcription factor Olig2 specifically in mature NG2 cells reduces the number of oligodendrocytes that are produced from NG2 cells in the adult brain. We have also performed a high throughput screen to identify compounds that upregulate Olig2 transcription. We will use these newly acquired tools to test the hypothesis that a critical level of Olig2 is required for successful remyelination in experimental autoimmune encephalomyelitis (EAE), which is a clinically relevant rodent model of MS. This will be tested in the following three specific aims. In Aim 1, we will determine whether loss of Olig2 will compromise the ability of NG2 cells to produce new oligodendrocytes in EAE lesions. In Aim 2, we will determine whether the newly identified compounds that increase Olig2 transcription activate the Sonic hedgehog-Gli pathway or the mitogen-activated protein kinase pathway and test compounds that affect different pathways for their ability to promote remyelination in EAE. In Aim 3, we will determine whether loss of Ezh2, which is a member of the Polycomb Repressor Complex responsible for methylating lysine 27 on histone H3, will promote remyelination by derepressing genes required for myelination.

描述（由申请人提供）：多发性硬化症（MS）是一种脱髓鞘疾病，影响了美国35万人，是慢性神经缺陷的主要原因，在他们一生中最活跃的成年人中影响成年人。再髓衰竭是MS长期和原发性病变的一个特征，与脉冲传导失败和轴突病理学有关。尽管再生衰竭的临床效果使人衰弱，但有些病变有效透露而另一些病变的原因尚不清楚。在整个成熟的中枢神经系统中，表达NG2蛋白聚糖（NG2细胞）的神经胶质细胞广泛存在。最近的遗传命运图研究提供了直接证明，它们不仅在发育过程中，而且在成熟的中枢神经系统中产生少突胶质细胞。使用我们已经生成的新的转基因小鼠系，我们观察到，在成熟的NG2细胞中特别降低了成人大脑中NG2细胞产生的少突胶质细胞的数量。我们还进行了高吞吐量屏幕，以识别上调寡核2转录的化合物。我们将使用这些新获得的工具来检验以下假设：在实验性自身免疫性脑脊髓炎（EAE）中成功再髓样需要临界的olig2水平，这是MS的临床相关啮齿动物模型。这将在以下三个特定目标中进行测试。在AIM 1中，我们将确定Olig2的丧失是否会损害NG2细胞在EAE病变中产生新的少突胶质细胞的能力。在AIM 2中，我们将确定新近鉴定的增加Olig2转录的化合物是否激活了声音刺猬-GLI途径或有丝分裂原激活的蛋白激酶途径和测试化合物，这些化合物会影响其在EAE中促进Remyelination的不同途径。在AIM 3中，我们将确定EZH2的损失是负责组蛋白H3上甲基化赖氨酸27的Polycomb抑制剂复合物的成员，它将通过髓鞘形成所需的解压缩基因来促进再髓鞘。