CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY

HIV 1 引起的神经元损伤的细胞机制

基本信息

  • 批准号:
    7959385
  • 负责人:
  • 金额:
    $ 6.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-05-01 至 2010-04-30
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neural progenitor cells (NPC) are critical for maintenance of CNS homeostasis. These cells persist throughout life and replenish neurons, astrocytes and oligodendrocytes as needed through a process referred to as neurogenesis. In neurodegenerative disorders, this process appears to be dysfunctional since dead or injured neurons, astrocytes and oligodendrocytes are not replaced. HIV associated dementia (HAD) is one of these disorders that has aroused significant interest. Recently, we demonstrated that CXCR4, an important co-receptor for HIV-1, was more highly expressed on human NPC than other chemokine receptors, and was coupled to downstream signaling systems. The intrinsic CXCR4 ligand, stromal cell-derived factor 1 (SDF-1), released in response to neuronal injury and astrocyte activation was also elevated in cerebral spinal fluids of HAD patients compared to infected subjects without neurological disorders. Recent studies have also shown that SDF-1 is cleaved by activated matrix metalloproteinase-2 (MMP-2) to form the highly neurotoxic SDF-1 (5-67). MMP-2 is also highly expressed on HIV-1-infected mononuclear phagocytes (MP), which play a central role in HAD. Neurogenesis is an emerging field and its role in HAD is poorly understood. This proposal examines the hypothesis that while activated astrocytes and injured neurons produce elevated levels of SDF-1 that promote neurogenesis, proteolysis of SDF-1 by enzymes released from HIV-1-infected MP could lead to an impairment of SDF-1/CXCR4 mediated neurogenic responses and prove detrimental to CNS repair. Using a newly developed human NPC culture system, we propose to study the role of SDF-1 (production, modification and function) in neurogenesis. We will use molecular manipulations, including gene silencing, and in vitro assays that mimic brain MP activation and innate CNS immune responses that occur in HAD, to examine the mechanisms of SDF-1 regulation. The knowledge gained from elucidating the mechanisms by which SDF-1/CXCR4 interact in neurogenesis may open up new therapeutic strategies for treating not only HAD but other neurodegenerative disorders.
这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者(PI)可能从另一个NIH来源获得了主要资金, 因此可以在其他CRISP条目中表示。所列机构为 研究中心,而研究中心不一定是研究者所在的机构。 神经前体细胞(NPC)是维持CNS稳态的关键。 这些细胞在整个生命中持续存在,并通过称为神经发生的过程根据需要补充神经元、星形胶质细胞和少突胶质细胞。 在神经退行性疾病中,由于死亡或受伤的神经元、星形胶质细胞和少突胶质细胞未被替换,因此该过程似乎功能失调。 艾滋病毒相关痴呆症(HAD)是引起人们极大兴趣的疾病之一。 最近,我们证明了CXCR 4,一个重要的辅助受体的HIV-1,更高的表达在人类NPC比其他趋化因子受体,并耦合到下游信号系统。内在CXCR 4配体,基质细胞衍生因子1(SDF-1),释放响应神经元损伤和星形胶质细胞活化也升高HAD患者的脑脊液相比,感染的受试者没有神经系统疾病。最近的研究还表明,SDF-1被活化的基质金属蛋白酶-2(MMP-2)切割,形成高度神经毒性的SDF-1(5-67)。 MMP-2也在HIV-1感染的单核吞噬细胞(MP)上高度表达,其在HAD中起核心作用。 神经发生是一个新兴的领域,其在HAD中的作用知之甚少。 该提案检验了以下假设:虽然活化的星形胶质细胞和受损的神经元产生促进神经发生的升高水平的SDF-1,但由HIV-1感染的MP释放的酶对SDF-1的蛋白水解可能导致SDF-1/CXCR 4介导的神经原性反应受损,并证明对CNS修复有害。利用新开发的人NPC培养系统,我们建议研究SDF-1在神经发生中的作用(生产,修饰和功能)。我们将使用分子操作,包括基因沉默,并在体外试验,模拟脑MP激活和先天性中枢神经系统免疫反应,发生在HAD,检查SDF-1的调节机制。从阐明SDF-1/CXCR 4在神经发生中相互作用的机制中获得的知识可能为治疗HAD和其他神经退行性疾病开辟新的治疗策略。

项目成果

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Jialin Charles Zheng其他文献

Jialin Charles Zheng的其他文献

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{{ truncateString('Jialin Charles Zheng', 18)}}的其他基金

Glutaminase and its neurotoxic link to HAND
谷氨酰胺酶及其与 HAND 的神经毒性联系
  • 批准号:
    9357733
  • 财政年份:
    2016
  • 资助金额:
    $ 6.69万
  • 项目类别:
Glutaminase and its neurotoxic link to HAND
谷氨酰胺酶及其与 HAND 的神经毒性联系
  • 批准号:
    9146113
  • 财政年份:
    2016
  • 资助金额:
    $ 6.69万
  • 项目类别:
ACTIVITY MODULATION OF PROTEIN KINASE AND PHOSPHATASE
蛋白激酶和磷酸酶的活性调节
  • 批准号:
    8362286
  • 财政年份:
    2011
  • 资助金额:
    $ 6.69万
  • 项目类别:
ACTIVITY MODULATION OF PROTEIN KINASE AND PHOSPHATASE
蛋白激酶和磷酸酶的活性调节
  • 批准号:
    8170287
  • 财政年份:
    2010
  • 资助金额:
    $ 6.69万
  • 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
  • 批准号:
    7869501
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
  • 批准号:
    7647340
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:
HIV-1 Clade Diversity and Macrophage Mediated Neurotoxicity in HIV-1 Dementia
HIV-1 进化枝多样性和巨噬细胞介导的 HIV-1 痴呆神经毒性
  • 批准号:
    7612649
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
  • 批准号:
    8026004
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
  • 批准号:
    8266024
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:
CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY
HIV 1 引起的神经元损伤的细胞机制
  • 批准号:
    7719942
  • 财政年份:
    2008
  • 资助金额:
    $ 6.69万
  • 项目类别:

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