Stem Cells And Neurogenesis

干细胞和神经发生

• 批准号: 8335818
• 负责人: Mark Mattson
• 金额: $ 3.93万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 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/8335818
• 关键词: Adult; Adverse effects; Affect; Alkaline Phosphatase; Alleles; Apical; Applied Research; Astrocytes; Axon; BHLH Protein; Basic Science; Binding; Blocking Antibodies; Botanicals; Brain; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; CXCR4 gene; Cell Fate Control; Cell Line; Cell Lineage; Cell Proliferation; Cells; Cerebral cortex; Coculture Techniques; Defect; Deoxyuridine; Development; Disease; Embryo; Embryonic Development; Enzymes; Epigenetic Process; Erinaceidae; Exhibits; Feedback; Flow Cytometry; Fluorescence-Activated Cell Sorting; Fostering; Gene Expression; Genetic; Genome; Germ; Glial Differentiation; Glial Fibrillary Acidic Protein; Glioblastoma; Glycolipids; Green Fluorescent Proteins; Growth; Histone H3; Human; Image; Injury; Integrin Binding; Integrins; Karyotype; Knowledge; Label; Laminin; Ligands; Mediating; Metabolic; Modeling; Molecular; Molecular Profiling; Molecular Weight; Morphology; Motor Neurons; Multiple Sclerosis; Mus; Myoblasts; Neocortex; Neonatal; Nervous system structure; Neuraxis; Neurologic; Neurons; Nitric Oxide; Octamer Transcription Factor-3; Oligodendroglia; Peptides; Pesticides; Phytochemical; Play; Population; Pregnancy; Production; Proliferating; Proliferating Cell Nuclear Antigen; Proteins; Radiation; Rattus; Recurrence; Regulation; Relative (related person); Reporting; Research; Resistance; Rodent; Role; Serotonin; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spinal Cord; Stat3 protein; Stem cells; System; TLR3 gene; Telencephalon; Time; Transcription Repressor/Corepressor; Transgenes; Transplantation; Traumatic Brain Injury; Tretinoin; Undifferentiated; Variant; Ventricular; Wild Type Mouse; Work; activating transcription factor; adhesion process; adult stem cell; base; brain cell; cancer stem cell; cell behavior; cytotoxicity; early embryonic stage; human embryonic stem cell; human embryonic stem cell line; immunocytochemistry; in utero; in vivo; inhibitor/antagonist; interdisciplinary approach; migration; monoamine; mortality; nerve stem cell; nervous system disorder; neurogenesis; neuroregulation; novel; novel strategies; plumbagin; pluripotency; postnatal; prevent; progenitor; protein expression; relating to nervous system; research study; response; self-renewal; stem; stem cell differentiation; stemness; telomere; therapeutic target; tool; tumor

We have made considerable progress towards understanding the cellular and molecular mechanisms that regulate the proliferation, differentiation and survival of neural progenitor cells in the developing and adult central nervous system. We found that nitric oxide and BDNF function in a positive feedback loop to promote neurogenesis. In other studies we found that SDFalpha, activates CXCR4 in glial progenitor cells resulting in increased migration and differentation of those cells. Our recent research has revealed a new molecular signaling system that regulates the fate of neural stem cells in the cerebral cortex. We used antibody-blocking and genetic experiments to reveal an requirement for laminin/integrin interactions in apical process adhesion and neural stem cell regulation. Transient abrogation of integrin binding and signalling using blocking antibodies to specifically target the ventricular region in utero results in abnormal cerebral cortex development. Using a multidisciplinary approach to analyse stem cell behaviour by expression of fluorescent transgenes and multiphoton time-lapse imaging revealed that the transient embryonic disruption of laminin/integrin signalling resulted in substantial layering defects in the postnatal neocortex. We have also investigated the roles of glial progenitor cells in the response of the nervous system to injury in models of traumatic brain injury and multiple sclerosis. This research is contributing to the development of novel approaches for treating neurological disorders based on treatments that stimulate stem cells to form new neurons that integrate into functional circuitry thereby reversing the damage caused by injury or disease. In other studies we found that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation embryonic day (E) 17.5, a deficit that persists in neonatal and adult mice. The results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Glioblastoma brain tumors harbor a small population of cancer stem cells that are resistant to conventional chemotherapeutic and radiation treatments, and are believed responsible for tumor recurrence and mortality. The identification of the epigenetic molecular mechanisms that control self-renewal of glioblastoma stem cells will foster development of targeted therapeutic approaches. The transcriptional repressor REST, best known for its role in controlling cell fate decisions in neural progenitor cells, may also be crucial for cancer stem cell self-renewal. We discovered that reduced TRF2 binding to REST targets REST for proteasomal degradation and thereby inhibits cancer stem cell proliferation. Neurological side effects of treatments that target REST and TRF2 may be less severe than conventional brain tumor treatments because postmitotic neurons do not express REST and have relatively stable telomeres. Recently,we found that TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3(-/-)-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain. In a recent screen of a panel of botanical pesticides, we identified plumbagin as having neuroprotective activity. Recently, we determined if plumbagin could modify the developmental fate of rat E14.5 embryonic neural progenitor cells (NPC). Plumbagin exhibited no cytotoxicity when applied to cultured NPC at concentrations below 1 microM. At a concentration of 0.1 muM, plumbagin significantly enhanced the proliferation of NPC as indicated by a 17% increase in the percentage of cells incorporating bromo-deoxyuridine. Plumbagin at a concentration of 0.1 pM (microM), stimulated the production of astrocytes as indicated by increased GFAP expression. Plumbagin selectively induced the proliferation and differentiation of glial progenitor cells without affecting the proliferation or differentiation of neuron-restricted progenitors. Plumbagin (0.1 pM) rapidly activated the transcription factor signal transducer and activator of transcription 3 (Stat3) in NPC, and a Stat3 inhibitor peptide prevented both plumbagin-induced astrocyte formation and proliferation. These findings demonstrate the ability of a low molecular weight naturally occurring phytochemical to control the fate of glial progenitor cells by a mechanism involving the Stat3 signaling pathway.

我们已经在了解调节增殖的细胞和分子机制方面取得了长足的进步 发展中心和成人中枢神经系统中神经祖细胞的分化和存活。 我们发现那一硝 氧化物和BDNF在阳性反馈循环中的功能以促进神经发生。 在其他研究中，我们发现SDFALPHA激活 神经胶质祖细胞中的CXCR4导致这些细胞的迁移和分化增加。 我们最近的研究表明 一种调节大脑皮质中神经干细胞命运的新分子信号系统。 我们使用了抗体阻滞和 基因实验揭示了对顶过程和神经干细胞中层粘连蛋白/整合素相互作用的需求 规定。使用阻断抗体的整合素结合和信号传导的瞬时废除，以特异性靶向心室 子宫内的区域会导致脑皮质异常的发育。 使用多学科方法分析干细胞行为 通过表达荧光转基因和多光子的延时成像，表明瞬态胚胎破坏 层粘连蛋白/整合素信号传导导致产后新皮层的大量分层缺陷。 我们还研究了神经胶质祖细胞在神经系统对创伤模型中损伤反应中的作用 脑损伤和多发性硬化症。 这项研究有助于开发用于治疗神经系统的新方法 基于刺激干细胞以形成新神经元的治疗疾病，从而逆转功能电路 受伤或疾病造成的损害。 在其他研究中，我们发现缺乏单胺代谢酶Mao A和Mao B（Mao AB缺陷小鼠）表现出的小鼠表现下降 从妊娠晚期胚胎日（e）17.5开始的脑脑脑中神经干细胞（NSC）的增殖，赤字 这持续存在于新生儿和成年小鼠中。结果表明，增殖能力依赖MAO的长期变化 NSC发生在胚胎发育后期，并由5-羟色胺介导。 胶质母细胞瘤脑肿瘤具有少数癌症干细胞，这些细胞对常规化学治疗性具有抗性 辐射处理，被认为是肿瘤复发和死亡率的原因。表观遗传分子的鉴定 控制胶质母细胞瘤干细胞自我更新的机制将促进靶向治疗方法的发展。这 转录阻遏物休息是以控制神经祖细胞中细胞命运决策的作用而闻名的，也可能是 对于癌症干细胞自我更新至关重要。 我们发现降低了TRF2与静止目标的结合，以使蛋白酶体降解 从而抑制癌症干细胞增殖。靶向休息和TRF2治疗的神经副作用可能较少 比常规的脑肿瘤治疗严重，因为有丝分裂后神经元没有表达休息，并且具有相对稳定的端粒。 最近，我们发现在发育的早期胚胎阶段和培养的神经中，脑细胞中存在TLR3蛋白 茎/祖细胞（NPC）。与来自TLR3缺陷型胚胎的NPC相比 野生型胚胎。通过磷酸组蛋白H3评估的增殖细胞数量和增殖细胞核抗原标记的数量， 与体内的野生型小鼠相比，TLR3缺陷型小鼠的发展皮质也增加了。培养的治疗 具有TLR3配体（PolyIC）的胚胎皮质神经球明显降低了增殖（BRDU标记）细胞和神经圈 野生类型的形成，而不是TLR3（ - / - ） - 派生的NPC。我们的发现揭示了TLR3在NPC负调节中的新作用 发育中的大脑增殖。 在最近的一批植物农药板的屏幕中，我们确定铅垂贴是具有神经保护活性的。 最近，我们 确定Plumbagin是否可以改变大鼠E14.5胚胎神经祖细胞（NPC）的发育命运。 Plumbagin展出 在浓度低于1微米的培养NPC上应用于培养的NPC时，没有细胞毒性。浓度为0.1妈妈，铅铅素显着 增强了NPC的增殖，如掺入Bromo-脱氧尿苷的细胞百分比增加了17％。铅锥 在浓度为0.1 pm时（microm），刺激了星形胶质细胞的产生，如GFAP表达增加所示。铅锥 选择性地诱导神经胶质祖细胞的增殖和分化，而不会影响增殖或 神经元限制祖细胞的分化。 Plumbagin（0.1 pm）迅速激活了转录因子信号传感器和 NPC中转录3（STAT3）的激活剂，而STAT3抑制剂肽则防止了铅脂蛋白诱导的星形胶质细胞形成和 增殖。这些发现证明了低分子量天然存在的植物化学能够控制命运的能力 胶质祖细胞通过涉及STAT3信号通路的机制。