Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain

炎症机制是衰老大脑中溶酶体衰竭的基础

基本信息

  • 批准号:
    9923516
  • 负责人:
  • 金额:
    $ 40.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-15 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

According to the Centers for Disease Control (CDC), 5 million Americans are living with Alzheimer's disease (AD), and another 2 million with Parkinson's disease (PD) and other late-onset neurodegenerative conditions (LO-NDs), yet to date, disease-modifying treatments for these diseases have remained elusive. While aging is the single greatest risk factor for LO-NDs, genome wide association studies (GWAS) have identified genes involved in regulation of lysosomes (vesicular organelles responsible for degrading and recycling damaged cellular material), and activation of inflammation and innate immunity, as LO-ND risk genes. However, to date, it is unclear how these two processes may interact in aging brain to promote the development of LO-NDs. Our data suggests that lysosomes may progressively fail during normal aging – even in the absence of a specific disease process or gene – and further suggest that low-grade induction of the innate immune enzyme, NADPH oxidase (Nox), by IL-6, may specifically result in lysosome failure in the aging brain. Exciting new data, below, shows that lysosomal failure in aging brain can be rescued by inhibition of Nox. Therefore based on recent literature, and our published and new observations, we propose that age-related lysosome failure is due to IL-6-mediated activation of NADPH oxidase, and propose mechanistic studies to test each component of this hypothesis. The premise behind this application, that inflammation in aging brain causes progressive failure of lysosomes, is supported by existing literature, our published studies, and new preliminary data, but has not been systematically studied. Aim 1 will test the hypothesis that lysosome failure during aging is due to inflammatory activation of Nox, and the corollary that Nox induction is mediated by Il-6 and STAT3 signaling. Our data showing that lysosomal function can be rescued by a Nox inhibitor in aging animals supports the first step in this hypothesis, and is to our knowledge the first to show that Nox inhibition can improve brain lysosome function. Unique mouse models, including PV-tdTomato, IL-6-/- and inducible neuronal Stat3-/- mice with high-resolution confocal microscopy will be used. Aim 2 will determine mechanistically how inflammation produces lysosome failure and impaired degradation of cargo in aging brain. Induced pluripotent stem cell (iPSC)-derived human neurons (iPSC-huNs), and aged mice treated with Nox-modifying agents will determine mechanisms impairing lysosome function. Aim 3 tests the hypotheses that extruded lysosomal cargo contains active proteases which then damage nearby cells including neurons, and that extruded lysosomal material (cargo) is pro-inflammatory. Imaging of cathepsin activity, neuronal injury and markers of microglial and astrocyte activation will be employed. IMPACT: Age-related diseases of the nervous system are an ever-increasing health care issue, but no disease-modifying treatments have emerged for these diseases. This proposal will advance our understanding of how inflammation impairs the ability of lysosomes to clear and recycle damaged cellular material to provide new treatment targets for neurodegenerative disorders.
根据疾病控制中心(CDC)的数据,有500万美国人生活在阿尔茨海默氏病 (AD),另外200万帕金森氏病(PD)和其他晚发神经退行性疾病 (LO-ND),但迄今为止,疾病改良的治疗仍然难以捉摸 LO-ND的最大危险因素,基因组广泛的关联研究(GWAS)已经鉴定了基因 参与溶酶体调节(囊泡细胞器,负责降解和招募受损受损的受损 细胞材料)和先天免疫的激活,迄今为止,它是LO-ND风险基因。 尚不清楚Tho过程如何在衰老中相互作用 数据表明,在正常衰老期间可能会逐渐失败 - 在没有特定的情况下 疾病过程或基因,进一步表明先天免疫酶的低度诱导NADPH IL-6的氧化酶(NOX)可能会导致衰老大脑的溶酶体衰竭。 表明可以通过抑制NOX来挽救衰老脑衰老的溶酶体衰竭。 文学以及我们已发表的新观察,我们建议与年龄有关的溶酶体失败到期 为IL-6介导的NADPH氧化酶的激活,并提出机械研究以测试每个成分 这个假设的前提。 溶酶体的失败得到了现有文献,我们已发表的研究和新的预序数据的支持,但已有 没有系统地研究AIM 1。 NOX的炎症激活,以及NOX诱导是由IL-6和STAT3介导的推论 信号传导。 据我们所知,该假设的第一步是第一个抑制NOx可以改善大脑 溶酶体功能。 使用高分辨率的共聚焦显微镜将确定机械性如何 炎症会产生溶酶体衰竭并在衰老大脑中的货物降解受损。 多能干细胞(IPSC)衍生的人神经元(IPSC-huns),并用NOX修饰治疗的老年小鼠 代理机制会损害溶酶体功能。 溶酶体货物包含活性蛋白酶,然后损坏附近包括神经元的细胞,并且 挤压溶酶体材料(货物)是促疾病的促疾病。 小胶质细胞和星形胶质细胞的标记将受到影响:与年龄有关的疾病 系统不断增加的医疗保健问题,但没有针对这些疾病的治疗方法 疾病。 清除并回收损坏的细胞材料,为神经衰弱障碍提供新的治疗靶标。

项目成果

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Laura L Dugan其他文献

Mitochondrial Uncoupling Proteins in the Central Nervous System Recommended Citation
中枢神经系统中的线粒体解偶联蛋白推荐引文
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jeong Sook;Kim;Laura L Dugan;Dugan;Laura L
  • 通讯作者:
    Laura L

Laura L Dugan的其他文献

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{{ truncateString('Laura L Dugan', 18)}}的其他基金

Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
  • 批准号:
    10514598
  • 财政年份:
    2019
  • 资助金额:
    $ 40.51万
  • 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
  • 批准号:
    9665155
  • 财政年份:
    2019
  • 资助金额:
    $ 40.51万
  • 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
  • 批准号:
    10043824
  • 财政年份:
    2019
  • 资助金额:
    $ 40.51万
  • 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
  • 批准号:
    10292955
  • 财政年份:
    2019
  • 资助金额:
    $ 40.51万
  • 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
  • 批准号:
    10159817
  • 财政年份:
    2018
  • 资助金额:
    $ 40.51万
  • 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
  • 批准号:
    10406349
  • 财政年份:
    2018
  • 资助金额:
    $ 40.51万
  • 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
  • 批准号:
    9293672
  • 财政年份:
    2010
  • 资助金额:
    $ 40.51万
  • 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
  • 批准号:
    8113936
  • 财政年份:
    2010
  • 资助金额:
    $ 40.51万
  • 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
  • 批准号:
    8292022
  • 财政年份:
    2010
  • 资助金额:
    $ 40.51万
  • 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
  • 批准号:
    8705765
  • 财政年份:
    2010
  • 资助金额:
    $ 40.51万
  • 项目类别:

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