Does Necroptosis Play a Role in Inflammation and Aging

坏死性凋亡在炎症和衰老中起作用吗

基本信息

  • 批准号:
    10454859
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is a major risk factor for both morbidity and mortality in the elderly humans. In addition, inflammation is a major risk factor for a variety of age-related diseases, e.g. type 2 diabetes, cardiovascular disease, cancer, neurodegenerative diseases, frailty, etc. Despite the link between inflammation, aging, and age-associated diseases, we do not know the molecular mechanism(s)/pathway(s) responsible for the chronic, low-grade inflammation seen in old animals and whether the increase in chronic inflammation is a causative factor in aging and age-related diseases. Necroptosis is a recently identified pathway of programmed necrosis that induces cell death through the lysis of cells, resulting in the release of damage-associated molecular patterns (DAMPs) from the dead cells. DAMPs are potent inducers of inflammation, and circulating DAMPs have been shown to increase with age in humans and to be strongly correlated to the level of inflammation in the individual. We hypothesize that necroptosis plays a role in chronic, low-grade inflammation, which occurs with age, and preventing necroptosis will attenuate inflammation, leading to increased lifespan, improved healthspan, and reduced age-related pathology. We will use genetically modified mouse models and a pharmacological intervention to block/reduce apoptosis by targeting the receptor-interacting protein kinases (RIPK) 1 or 2 and mixed lineage kinase domain like (MLKL) protein, which are involved in the initiation of necroptosis. Aim1. Determine the role of necroptosis in chronic inflammation that occurs with age and the types of cells undergoing necroptosis. We will determine the effect of reducing necroptosis either genetically (using Ripk3+/-, Ripk3-/-, Mlkl+/-, and Mlkl-/- mice) or pharmacologically (treating with necrostatin-1s, a RIPK1 inhibitor) on inflammation. We will also identify the cell type(s) that undergo necroptosis in selected tissues of old mice. Based on our hypothesis, we predict that those tissues showing an up-regulation in necroptosis with age will show an increase in production of proinflammatory cytokines and reducing/blocking necroptosis will decrease inflammation in these tissues as well as circulating levels of proinflammatory cytokines. Aim2. Identify the pathways that increase necroptosis with age and determine the mechanism(s) that mediates the age-related increase in inflammation arising from necroptosis. TNFα, oxidative stress, and mTOR signaling have been proposed to initiate necroptosis, and these pathways increase with age. In Aim 2, we determine the role of these pathways play in the age-related increase in necroptosis using specific inhibitors to each of the pathways. DAMPs released by necroptotic cells induce inflammation through activation of three pathways: the IKK-NF-κB, MAPK-AP1 and inflammasome pathways. In Aim 2, we will also assess the effect of age on the activation of these pathways in various tissues of WT mice and determine which of the pathways are reduced when necroptosis is reduced/blocked in Ripk3 and Mlkl knockout mice or by necrostatin-1s treatment. Aim3. Determine the role of necroptosis in aging. In Aim 3, two groups of mice in which necroptosis has been blocked/reduced will be compared to wildtype mice. Mouse models (e.g., Ripk3 and/or Mlkl knockout mice) will be used that we find block inflammaging in Aim 1. The lifespan, healthspan (e.g., activity, rotarod performance, grip strength, insulin sensitivity, cognition, etc.), and age-associated pathology of these mice will be compared to WT mice. Based on our hypothesis, we predict that reducing/blocking necroptosis will retard aging as shown by improved healthspan, reduced pathology, and increased lifespan. These data would provide the first direct evidence that necroptosis induced inflammation is directly involved in aging and that chronic, low-grade inflammation plays a role in aging and the increase in pathology and age-related diseases.
慢性、低度炎症(炎症)是衰老的标志,也是衰老和衰老的主要危险因素 老年人的发病率和死亡率。此外,炎症是多种疾病的主要危险因素。 与年龄有关的疾病,例如2型糖尿病、心血管疾病、癌症、神经退行性疾病、 尽管炎症、衰老和与年龄相关的疾病之间存在联系,但我们并不知道 导致老年动物慢性、低度炎症的分子机制/途径 以及慢性炎症的增加是否是衰老和与年龄相关的疾病的致病因素。 坏死性凋亡是最近发现的一种程序性坏死途径,通过裂解诱导细胞死亡 细胞,导致死亡细胞释放损伤相关分子模式(DAMP)。 DAMP 是炎症的有效诱导剂,循环 DAMP 已被证明随着年龄的增长而增加 人类,并与个体的炎症水平密切相关。我们假设 坏死性凋亡在慢性、低度炎症中发挥作用,这种炎症随着年龄的增长而发生,并预防 坏死性凋亡会减轻炎症,从而延长寿命,改善健康状况, 减少与年龄相关的病理。我们将使用转基因小鼠模型和药理学 通过针对受体相互作用蛋白激酶 (RIPK) 1 或 2 进行干预以阻止/减少细胞凋亡,以及 混合谱系激酶结构域样 (MLK​​L) 蛋白,参与坏死性凋亡的启动。 目标1。确定坏死性凋亡在随年龄和类型而发生的慢性炎症中的作用 细胞发生坏死性凋亡。我们将通过基因确定减少坏死性凋亡的效果(使用 Ripk3+/-、Ripk3-/-、Mlkl+/- 和 Mlkl-/- 小鼠)或药理学(用 RIPK1 抑制剂 necrostatin-1s 治疗) 关于炎症。我们还将鉴定在老年小鼠的选定组织中发生坏死性凋亡的细胞类型。 根据我们的假设,我们预测那些随着年龄的增长而表现出坏死性凋亡上调的组织将 显示促炎细胞因子的产生增加,减少/阻止坏死性凋亡将会减少 这些组织的炎症以及促炎细胞因子的循环水平。 目标2。确定随着年龄增长而增加坏死性凋亡的途径,并确定导致坏死性凋亡的机制 介导坏死性凋亡引起的与年龄相关的炎症增加。 TNFα、氧化应激和 mTOR 信号传导被认为可以引发坏死性凋亡,并且这些途径随着年龄的增长而增加。在目标 2 中, 我们使用特定的方法确定这些途径在与年龄相关的坏死性凋亡增加中所起的作用 每个途径的抑制剂。坏死性凋亡细胞释放的 DAMP 通过以下方式诱导炎症: 激活三个途径:IKK-NF-κB、MAPK-AP1 和炎症小体途径。在目标 2 中,我们还将 评估年龄对 WT 小鼠各种组织中这些途径激活的影响,并确定 当 Ripk3 和 Mlkl 敲除小鼠的坏死性凋亡减少/阻断时,哪条途径会减少,或者 通过 necrostatin-1s 治疗。 目标3。确定坏死性凋亡在衰老中的作用。在目标 3 中,两组出现坏死性凋亡的小鼠 将被阻断/减少的小鼠与野生型小鼠进行比较。小鼠模型(例如 Ripk3 和/或 Mlkl 敲除 将使用我们在目标 1 中发现的阻止炎症的小鼠)。寿命、健康寿命(例如活动、旋转棒) 这些小鼠的表现、握力、胰岛素敏感性、认知等)以及与年龄相关的病理学将 与WT小鼠进行比较。根据我们的假设,我们预测减少/阻止坏死性凋亡将延缓 衰老表现为健康状况改善、病理减少和寿命延长。这些数据将 提供了第一个直接证据表明坏死性凋亡诱导的炎症直接参与衰老并且 慢性、低度炎症在衰老以及病理学和与年龄相关的疾病的增加中发挥着作用。

项目成果

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ARLAN G. RICHARDSON其他文献

ARLAN G. RICHARDSON的其他文献

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{{ truncateString('ARLAN G. RICHARDSON', 18)}}的其他基金

BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10451497
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10618254
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Does Necroptosis Play a Role in Inflammation and Aging
坏死性凋亡在炎症和衰老中起作用吗
  • 批准号:
    9913983
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Does Necroptosis Play a Role in Inflammation and Aging
坏死性凋亡在炎症和衰老中起作用吗
  • 批准号:
    10166597
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for Cell Sorter
ShEEP 请求细胞分选仪
  • 批准号:
    9906780
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
ADMINISTRATIVE SUPPLEMENT TO GRANT R01-AG057424, Short-term Measurements of Physical Resilience as a Predictor of Healthspan in Mice.
授予 R01-AG057424 的行政补充,短期身体弹性测量作为小鼠健康寿命的预测因子。
  • 批准号:
    9752040
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
TESTING THE ABILITY OF NOVEL ASSAYS OF RESILIENCE TO PREDICT LIFESPAN
测试新的弹性分析方法预测寿命的能力
  • 批准号:
    10165438
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Oklahoma Nathan Shock Center of Excellence in Basic Biology of Aging
俄克拉荷马州内森休克衰老基础生物学卓越中心
  • 批准号:
    10404833
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Oklahoma Nathan Shock Center of Excellence in Basic Biology of Aging
俄克拉荷马州内森休克衰老基础生物学卓越中心
  • 批准号:
    9110089
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Program Enhancement Core
程序增强核心
  • 批准号:
    10424597
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:

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