PD-Ialpha/ATX's role for forebrain oligodendrocyte specification and migration

PD-Ialpha/ATX 在前脑少突胶质细胞规范和迁移中的作用

• 批准号: 7595242
• 负责人: BABETTE FUSS
• 金额: $ 3.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595242
• 关键词: Active Sites; Address; Adhesives; Adult; Affect; Applications Grants; Area; Attention; Award; Axon; Behavior; Biology; Brain; Brazil; Cell Cycle; Cell physiology; Cells; Cerebrospinal Fluid; Collaborations; Complex; Cues; Cytoskeleton; DNA Sequence Rearrangement; Data; Demyelinating Diseases; Development; Embryo; Environment; Epithelial Cells; Event; Extracellular Matrix; Fibrinogen; Focal Adhesions; Funding; Gene Expression; Generations; Goals; Grant; Guidelines; Human; Image; Immigration; Immunohistochemistry; Injection of therapeutic agent; Injury; Integrins; Investigation; Knowledge; Label; Laboratories; Lead; Life; Location; Lysophosphatidic Acid Receptors; Lysophospholipids; Mammalian Cell; Mediating; Membrane; Metalloproteases; Molecular; Morphology; Multiple Sclerosis; Myelin; Myelin Sheath; Nerve Degeneration; Nervous System Physiology; Neural Conduction; Neuraxis; Neurodegenerative Disorders; Neurons; Oligodendroglia; Parents; Pathway interactions; Pattern; Phosphodiesterase I; Phospholipids; Principal Investigator; Process; Proliferating; Prosencephalon; Proteins; Rodent; Role; Signal Transduction; Site; Small Interfering RNA; Spinal Cord; Staging; Stem cells; Structure; Structure of choroid plexus; System; Therapeutic; Time; Tissue Donors; Transplantation; United States National Institutes of Health; Universities; autocrine; base; blastomere structure; cell fate specification; cell motility; cell type; cost; extracellular; in vivo; insight; lysophosphatidic acid; migration; myelination; nerve stem cell; nervous system development; nervous system disorder; novel; oligodendrocyte lineage; oligodendrocyte precursor; paracrine; parent grant; phosphoric diester hydrolase; postnatal; public health relevance; relating to nervous system; release factor; repaired; research study; rho GTP-Binding Proteins; stem; subventricular zone; white matter

DESCRIPTION (provided by applicant): The mature mammalian central nervous system (CNS) possesses only a restricted ability to repair itself, mainly due to its limited capacity in generating and properly targeting new neural cell types. The long-term goal of the proposed studies is to better understand the regulatory circuits that may be necessary for stimulating CNS-resident neural stem/progenitor cells for repair of the CNS and in particular the myelin sheath that is a prerequisite for fast and efficient nerve conduction. More specifically, the current proposal investigates the central hypothesis that the choroid plexus released protein phosphodiesterase-Ialfa/autotaxin (PD-Ialfa/ATX), via its enzymtically active lyso-PLD site, represents one of the factors regulating cell fate and migration of myelinating cells, i.e. oligodendrocytes (OLGs), in the postnatal mammalian forebrain. The studies described in the two Specific Aims of the proposal and addressing the above central hypothesis will be done primarily at the Federal University of Rio de Janeiro (Brazil) in collaboration with Cecilia Hedin-Pereira as an extension to NIH grant 5R01NS045883. In Specific Aim 1, we will determine the role of PD-Ialfa/ATX and in particular its lysoPLD-active site for OLG cell fate determination in the rodent forebrain. OLG specification has been shown to occur in the postnatal forebrain within a specialized region, namely the subventricular zone (SVZ). We will investigate the effects of lysophosphatidic acid (LPA), the endproduct of PD-Ialfa/ATX's enzymatic activity, fully functional PD-Ialfa/ATX and enzymatically inactive PD-Ialfa/ATX on OLG cell fate specification using SVZ explant cultures. To further characterize the LPA/PD-Ialfa/ATX-mediated effects on the OLG lineage, we will assess the contribution of the known LPA receptors by using pharmacological and siRNA approaches. In addition, we will perform in vivo experiments, in which cycling cells of the SVZ will be labeled using retroviral injections. PD-Ialfa/ATX and enzymatically inactive PD-Ialfa/ATX will additionally be injected and the effects on cell fate specification will be determined using immunohistochemistry and confocal imaging. In Specific Aim 2, we will determine the role of PD-Ialfa/ATX and in particular its lysoPLD-active site for migration of newly generated OLG progenitor cells (OPCs) within the rodent forebrain. We will use the same experimental paradigms as used in the studies to Specific Aim 1. Here we will, however, focus our analysis on the migratory pathways of OPCs. Taken together, the proposed sets of experiments are expected to yield novel insight into the regulatory mechanisms that control 1) OLG specification and 2) OPC migration in the developing forebrain. Most importantly, these studies are anticipated to lead to subsequent investigations aimed at stimulating endogenous neural stem/progenitor cells to contribute to repair of the myelin sheath under pathological conditions. Public Health Relevance: The mature mammalian central nervous system (CNS) possesses only a restricted ability to repair itself after injury and under pathological conditions. Stimulation of CNS-resident neural stem/progenitor cells represents a promising, yet currently poorly characterized, possibility for restoring CNS function including fast and efficient nerve conduction that is ultimately dependent on the presence of an undamaged myelin sheath. As an attempt to better understand the regulatory circuits that may be necessary for stimulating endogenous repair of the myelin sheath, the present grant application investigates the potential role of the extracellular factor phosphodiesterase-Ialfa/autotaxin (PD-Ialfa/ATX) in stimulating the generation and migration of myelinating cells, i.e. oligodendrocytes.

描述（由申请人提供）：成熟的哺乳动物中枢神经系统（CNS）仅具有修复自身修复的限制能力，这主要是由于其产生和适当靶向新的神经细胞类型的能力有限。拟议的研究的长期目标是更好地了解刺激CNS居住的神经干/祖细胞所必需的调节回路，以修复CNS，尤其是髓鞘鞘，这是快速有效的神经传导的先决条件。 More specifically, the current proposal investigates the central hypothesis that the choroid plexus released protein phosphodiesterase-Ialfa/autotaxin (PD-Ialfa/ATX), via its enzymtically active lyso-PLD site, represents one of the factors regulating cell fate and migration of myelinating cells, i.e. oligodendrocytes (OLGs), in the postnatal mammalian前脑。该提案的两个具体目的和上述中心假设中描述的研究将主要是在里约热内卢联邦大学（巴西）与塞西莉亚·赫迪因·佩雷拉（Cecilia Hedin-Pereira）合作，以扩展NIH授予5R01NS04583。在特定的目标1中，我们将确定pd-airfa/atx的作用，尤其是其在啮齿动物前脑中的OLG细胞命运确定的lysopld活性位点。 OLG规范已显示出在特殊区域内的产后前脑中发生，即室室下区（SVZ）。我们将研究溶物磷脂酸（LPA），PD-EILFA/ATX酶活性的最终产物，功能齐全的PD-EILFA/ATX以及酶非活动的PD-EILFA/ATX对使用SVZ Explant培养物对OLG细胞命运规范的影响。为了进一步表征LPA/PD-EIALFA/ATX介导的对OLG谱系的影响，我们将使用药理和siRNA方法评估已知LPA受体的贡献。此外，我们将进行体内实验，其中将使用逆转录病毒注射标记SVZ的循环细胞。 PD-EIALFA/ATX和酶无效的PD-EILFA/ATX还将进一步注射，并将使用免疫组织化学和共聚焦成像确定对细胞命运规范的影响。在特定的目标2中，我们将确定pd-ialfa/atx，尤其是其lysopld活性位点在啮齿动物前脑内新产生的OLG祖细胞（OPC）迁移的作用。我们将使用与研究中使用的相同的实验范例来特定目标1。但是，在这里，我们将把分析集中在OPC的迁移途径上。综上所述，提出的一组实验有望产生对控制的调节机制的新洞察力1）OLG规范和2）在发育中的前脑中的OPC迁移。最重要的是，这些研究预计会导致随后的研究旨在刺激内源性神经茎/祖细胞，从而有助于在病理条件下修复髓鞘。公共卫生相关性：成熟的哺乳动物中枢神经系统（CNS）仅具有受伤后和病理状况下修复自身的限制能力。刺激CNS居住的神经茎/祖细胞代表了恢复中枢神经系统功能的可能性但目前较差的可能性，包括快速有效的神经传导，最终取决于未损坏的髓鞘的存在。为了更好地了解刺激内源性修复髓鞘所必需的调节电路，目前的赠款申请研究了细胞外因子磷酸二酯酶-IALFA/自身X.蛋白（PD-EIALFA/ATX）在刺激骨髓细胞的产生和迁移髓细胞（I.Ee.OligodeDeSenteS）中的潜在作用。