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相当大的进展， 神经祖细胞在发育和成年中枢神经系统中的分化和存活。 我们发现硝酸 氧化物和BDNF在正反馈回路中起作用以促进神经发生。 在其他研究中，我们发现SDF α，激活 CXCR4在神经胶质祖细胞中的表达导致这些细胞的迁移和分化增加。 我们最近的研究显示 一种新的分子信号系统，调节大脑皮层神经干细胞的命运。 我们使用抗体阻断， 遗传学实验揭示层粘连蛋白/整合素相互作用在顶突粘附和神经干细胞中的要求 调控使用特异性靶向心室肌细胞的阻断抗体瞬时消除整联蛋白结合和信号传导 在子宫内的区域导致异常的大脑皮层发育。 使用多学科方法分析干细胞行为 通过荧光转基因的表达和多光子延时成像显示， 层粘连蛋白/整联蛋白信号传导导致出生后新皮质中的实质性分层缺陷。 我们还研究了神经胶质祖细胞在创伤模型中神经系统对损伤的反应中的作用。 脑损伤和多发性硬化症 这项研究有助于开发治疗神经系统疾病的新方法。 基于刺激干细胞形成新神经元的治疗方法的疾病，这些新神经元整合到功能电路中，从而逆转 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的小鼠（MAO AB缺陷小鼠）表现出降低的 在妊娠晚期胚胎天（E）17.5开始，发育中的端脑中神经干细胞（NSC）的增殖， 在新生和成年小鼠中持续存在。结果表明，单胺氧化酶依赖性的长期改变的增殖能力， 神经干细胞的增殖在胚胎发育后期发生，由5-羟色胺介导。 胶质母细胞瘤脑肿瘤含有一小群对常规化疗和化疗药物具有抗性的癌症干细胞。 放射治疗，并且被认为是肿瘤复发和死亡的原因。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。的 转录抑制因子REST，以其在控制神经祖细胞中的细胞命运决定中的作用而闻名，也可能是 对癌症干细胞的自我更新至关重要。 我们发现，减少TRF2与REST的结合可以靶向REST进行蛋白酶体降解， 从而抑制癌症干细胞增殖。针对REST和TRF2的治疗的神经副作用可能更少 比传统的脑肿瘤治疗更严重，因为有丝分裂后的神经元不表达REST，并且具有相对稳定的端粒。 最近，我们发现TLR3蛋白存在于早期胚胎发育阶段的脑细胞中，以及培养的神经细胞中。 干/祖细胞（NPC）。来自TLR3缺陷胚胎的NPC形成的神经球数量多于来自 野生型胚胎通过磷酸化组蛋白H3和增殖细胞核抗原标记评估的增殖细胞数量， 与野生型小鼠相比，在体内TLR3缺陷小鼠的发育皮质中也增加。处理培养 具有TLR3配体（polyIC）的胚胎皮质神经球显著减少增殖（BrdU标记）细胞和神经球 在野生型但不是TLR3（-/-）衍生的NPC中形成。我们的研究结果揭示了TLR3在NPC负调控中的新作用 在发育中的大脑中增殖。 在最近的一次植物杀虫剂小组的筛选中，我们确定了白花丹素具有神经保护活性。 最近我们 确定白花丹素是否可以改变大鼠E14.5胚胎神经祖细胞（NPC）的发育命运。Plumbagin展示了 当浓度低于1 μ M时应用于培养的NPC时，没有细胞毒性。在0.1 μ M的浓度下，白花丹素显著地 增强NPC的增殖，如掺入溴脱氧尿苷的细胞百分比增加17%所示。丹素 浓度为0.1 pM（μ M）时，刺激星形胶质细胞的产生，如GFAP表达增加所示。丹素 选择性地诱导胶质祖细胞的增殖和分化，而不影响增殖或 神经元限制性祖细胞的分化。白花丹素（0.1 pM）快速激活转录因子信号转导子， 转录激活因子3（Stat3）和Stat3抑制肽阻止白花丹素诱导的星形胶质细胞形成， 增殖这些发现证明了低分子量天然存在的植物化学物质控制命运的能力。 神经胶质祖细胞的Stat3信号通路的机制。