Stem Cells And Neurogenesis

干细胞和神经发生

基本信息

  • 批准号:
    8335818
  • 负责人:
  • 金额:
    $ 3.93万
  • 依托单位:
  • 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:
  • 项目状态:
    未结题

项目摘要

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,

项目成果

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Mark Mattson其他文献

Mark Mattson的其他文献

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{{ truncateString('Mark Mattson', 18)}}的其他基金

Stem Cells And Neurogenesis
干细胞和神经发生
  • 批准号:
    7591990
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Apoptosis In Neurodegenerative Disorders
神经退行性疾病中的细胞凋亡
  • 批准号:
    8736518
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Hormesis/Adaptive Stress Responses and Aging
毒物兴奋/适应性应激反应和衰老
  • 批准号:
    8736526
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Neuroprotective And Neurorestorative Signaling Mechanisms
神经保护和神经恢复信号机制
  • 批准号:
    8552362
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Cellular And Molecular Pathogenesis Of Alzheimer
阿尔茨海默病的细胞和分子发病机制
  • 批准号:
    8736517
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Synaptic Plasticity In Aging And Neurodegenerative Disorders
衰老和神经退行性疾病中的突触可塑性
  • 批准号:
    8736521
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Dietary Modification Of Brain Aging And Alzheimer's Disease
大脑衰老和阿尔茨海默病的饮食调整
  • 批准号:
    9770106
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Dietary Modification Of Brain Aging And Neurodegenerative Disorders
大脑衰老和神经退行性疾病的饮食调整
  • 批准号:
    8148215
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Hormesis/Adaptive Stress Responses and Aging
毒物兴奋/适应性应激反应和衰老
  • 批准号:
    8335823
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:
Neuroprotective And Neurorestorative Signaling Mechanisms
神经保护和神经恢复信号机制
  • 批准号:
    8931506
  • 财政年份:
  • 资助金额:
    $ 3.93万
  • 项目类别:

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  • 资助金额:
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