Modulation of Post-Ischemic Astrogliosis by Human Glial Progenitor Cells

人胶质祖细胞对缺血后星形胶质细胞增生的调节

基本信息

批准号：
7752596
负责人：
STEVEN Alan GOLDMAN
金额：
$ 38.36万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7752596
关键词：
Acute Acute Brain Injuries Address Adjustment Disorders Adult Animals Astrocytes Astrocytosis Attention Attenuated BMP4 Beds Binding Biological Availability Blood Vessels Brain Bromodeoxyuridine Calmodulin Cell Count Cell Differentiation process Cell Maintenance Cells Chondroitin Sulfate Proteoglycan Chondroitinases Cicatrix Competence Critiques Data Deposition Disease Environment Epilepsy Exercise Experimental Designs Extracellular Matrix FGF9 gene FGFR3 gene Family Financial compensation Frequencies Gene Expression Generations Genes Genetic Genomics Glean Glial Differentiation Gliosis Goals Heparin Binding Homeostasis Human Hyaluronidase Hypertensive Encephalopathy Hypoxia Image Immigration In Vitro Incidence Individual Infection Infiltration Inflammation Inflammatory Injury Intention Ions Ischemic Stroke Knowledge Label Learning Ligands Mediating Methodology Methods Molecular Moon Natural regeneration Nerve Degeneration Neurons Oligodendroglia Paper Pathology Pathway interactions Pattern Phenotype Platelet-Derived Growth Factor Play Population Preparation Principal Investigator Procedures Production Protein Tyrosine Kinase Protein Tyrosine Phosphatase Protein-Serine-Threonine Kinases Proteolysis Publishing RNA RNA Interference Reagent Regulation Research Personnel Role Running Sample Size Sampling Seizures Signal Pathway Signal Transduction Sorting - Cell Movement Source Specificity Spinal Cord Stem cells Stroke System Systems Analysis Testing Time Tissues Transactivation Translating Transplantation Trauma Uncertainty Undifferentiated Validation Viral Voice Work astrogliosis autocrine base brain tissue daughter cell diabetic experience gliogenesis heparin proteoglycan in vivo in vivo Model indexing inhibitor/antagonist knock-down paracrine pleiotrophin prevent progenitor programs proto-oncogene protein kfgf receptor reconstruction regenerative relating to nervous system research study response self-renewal syndecan trafficking trait vector white matter

项目摘要

There is an abundant pool of glial progenitor cells (GPCs) dispersed throughout adult human brain tissue. This proposal seeks to define the niche for astrogliogenesis in the human white matter, with an emphasis on defining the molecular basis for reactive astrocytosis. Absent autocrine and paracrine influences, adult GPCs are not restricted to any given neural lineage. Rather, the environment regulates their differentiated fate, suggesting that an ischemic environment might specifically direct GPCs to astrocytic fate in reactive astrocytosis. On this basis, we investigated the gene expression patterns of adult human GPCs derived from normal brain tissue. We identified a set of parallel and interacting ligand-receptor interactions, as well as their cognate signaling pathways, that may to determine whether a given GPC remains undifferentiated, or instead develops into an astrocyte, oligodendrocyte, or neuron. We now propose to define those pathways involved in both normal and post-ischemic astrocytosis from adult human glial progenitors. By this means, we expect to identify genetic and pharmacological targets by which to suppress reactive astrocytosis following ischemic injury, while sustaining our ability to mobilize progenitors to desired lineages. To this end, we shall focus on several pathways that appear differentially expressed in isolated GPCs. These include receptor tyrosine phosphatase-p/^ (RTPZ), which may play a central role in modulating li-catenin trafficking, its chondroitin sulfate proteoglycan ligands, and two interacting receptor systems, the FGFR3 tyrosine kinase, and the BMP4-dependent serine/threonine kinases. Specifically, weask: 1. Does the inhibition of RTPZ signaling suppress astrocytosis in vitro? Is this effect mediated by impeding B-catenin translocation? Can RTPZ inhibition suppress glial scar formation in vivo? What are the functional effects of suppressing post-ischemic gliosis through RTPZ inhibition? 2. Can reactive astrocytosis and glial scar formation after stroke be prevented by inhibiting BMP4-signaled astrocyte induction? What BMP inhibitors are best for this purpose? 3. How does the RTPZ pathway interact with FGFR3 and BMP signaling to instruct astrocytic fate? 4. Does the expression of CSPGs by GPCs produce an environment biased to astrocytosis, through CSPG-dependent activation of RTPZ? Can astrocytosis be suppressed through CSPG inactivation? Can concurrent RTPZ suppression further attenuate gliosis? What are the functional consequences of these strategies, in particular after MCA occlusion? The implications of this work are profound, not only in regards to stroke and trauma, but more broadly with regards to diabetic and hypertensive encephalopathies, which share an hypoxia-triggered disruption of the normal niches for cell genesis in the brain. In each of these disorders, reactive astrocytosis culminates in the sclerotic pathology that typifies terminally non-regenerative brain and spinal cord. Our goal is too prevent this fate, and by so doing preserve the cellular plasticity and regenerative capabilities of the healthy CNS.

在成年人类脑组织中分散了大量的神经胶质祖细胞（GPC）。该建议旨在定义人类白质中星形胶质发生的利基，重点是定义反应性星形细胞增多症的分子基础。缺乏自分泌和旁分泌影响，成人GPC 不限于任何给定的神经谱系。相反，环境调节其差异化的命运，暗示缺血环境可能会专门将GPC引向反应性的星形胶质细胞命运星形细胞增多症。在此基础上，我们研究了成人人GPC的基因表达模式正常的脑组织。我们确定了一组平行和相互作用的配体 - 受体相互作用，以及它们的同源信号通路，可以确定给定的GPC是否保持未分化或而是发展成星形胶质细胞，少突胶质细胞或神经元。我们现在建议定义这些途径参与成人人神经胶质祖细胞的正常和缺血后星形细细胞增多症。这意味着，我们期望确定抑制反应性星形细胞增多症的遗传和药理靶标缺血性损伤后，同时维持我们动员祖细胞到所需谱系的能力。为此，我们将专注于几种在孤立的GPC中差异表达的途径。这些包括受体酪氨酸磷酸酶-P/^（RTPZ），可能在调节李 - 蛋白运输中起核心作用，其硫酸软骨素蛋白聚糖配体和两个相互作用的受体系统FGFR3酪氨酸激酶和BMP4依赖性丝氨酸/苏氨酸激酶。特别是，韦斯克： 1。抑制RTPZ信号传导是否会在体外抑制星形细胞增多症？这种效应是由阻碍B-catenin易位？ RTPZ抑制可以抑制体内的神经胶质疤痕形成吗？什么是通过RTPZ抑制抑制缺血后神经胶质病的功能效应？ 2。可以反应性星形细胞增多症通过抑制BMP4信号的星形胶质细胞诱导，可以预防中风后的神经胶质疤痕？什么 BMP抑制剂最适合此目的吗？ 3。RTPZ途径如何与FGFR3和BMP相互作用信号传导指导星形胶质性命运？ 4。GPC的CSPG表达是否会产生环境通过RTPZ的CSPG依赖性激活对星形胶质细胞增多症有偏见？可以抑制星形细胞增多症吗通过CSPG灭活？并发RTPZ抑制可以进一步减弱神经胶质变性吗？什么是这些策略的功能后果，尤其是MCA阻塞后？这项工作的含义是深刻的，不仅在中风和创伤方面，而且更广泛地关于糖尿病和高血压性脑病，这具有低氧触发的破坏大脑细胞起源的正常壁细分。在这些疾病中的每一个中，反应性星形细胞增多都达到顶点典型的硬化性病理学是末端非再生性脑和脊髓。我们的目标是太防止了这种命运，并因此保留了健康中枢神经系统的细胞可塑性和再生能力。