Intracellular nucleic acid sensing and age-related chronic inflammation

细胞内核酸传感与年龄相关的慢性炎症

基本信息

  • 批准号:
    10329935
  • 负责人:
  • 金额:
    $ 41.65万
  • 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:
    2019-02-22 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

Chronic inflammation is a common pathological basis for age-associated increases in autoimmunity, diabetes, cancer, cardiovascular and Alzheimer’s disease as well as shortened lifespan. Failure to resolve an activated innate immune response contributes significantly to chronic inflammation. Despite the profound clinical implications, the specific innate pathways contributing to chronic inflammation remain unknown. We reasoned that age-associated accrual of damaged DNA, which in other settings is a known driver of inflammation through cell-intrinsic DNA-sensing pathways, may contribute to age-associated chronic inflammation through these same innate pathways. Notably, cell-intrinsic DNA-sensing pathways require the participation of the DNA-sensor, cGAS and ER-resident adaptor, STING and are potent inducers of the pleiotropic cytokine family, type I interferons (IFN-I). IFN-I have been linked to chronic inflammation in disorders such as autoimmunity and cancer. While the molecular components of age-associated chronic inflammation remain undefined, a significant body of work suggests that recirculating innate cells may be compromised, however, the contribution of tissue resident macrophages to aging has not been addressed. Tissue macrophages are distinct from other myeloid-derived cells, not only in their origins, but also because they integrate epigenetic and microenvironment cues to carry out a unique set of functions. In addition to mounting innate immune responses, tissue macrophages are indispensable for tissue patterning, resolution of inflammation and tissue repair. Here we propose to test the hypothesis that cytosolic DNA-sensing promotes constitutive IFN-I induction within tissue macrophages and drives age-associated chronic inflammation. We will systematically address how specific innate processes contribute to immune dysfunction in the elderly in three specific aims. 1) We will evaluate the contribution of cytosolic DNA-sensing pathways to aging-associated constitutive IFN-I and proinflammatory signatures in tissues and resident macrophages using mice deficient in cGAS and STING. 2) We will determine the direct contribution cytosolic DNA sensing pathways in exclusively shaping tissue macrophage fate and function with age by conditionally deleting STING directly in tissue macrophage progenitors. As the epigenomes and transcriptomes of tissue macrophages are highly plastic, we will utilize next generation sequencing to identify genome-wide changes instigated by cytosolic DNA-sensing pathways in these cells with progressive age. 3) Finally, we will extend our findings to humans and determine the baseline IFN-I signatures and responsiveness of tissue macrophages from the lungs of geriatric patients and correlate them to well-represented loss-of-function haplotypes of STING. By uncovering the molecular details of chronic inflammation in aging humans, the findings from this study offer new immunomodulatory strategies and targets to bolster protective immunity as well as block detrimental inflammation, as desired, during aging.
慢性炎症是与年龄相关的自身免疫增加的常见病理基础, 糖尿病、癌症、心血管和阿尔茨海默病以及寿命缩短。未能解决 激活的先天免疫应答显著地促成慢性炎症。尽管意义深远 临床意义,具体的先天途径有助于慢性炎症仍然未知。我们 他推断,与年龄相关的受损DNA的增加,在其他情况下,这是一个已知的驱动因素, 炎症通过细胞内在的DNA传感途径,可能有助于与年龄相关的慢性 炎症通过这些相同的先天途径。值得注意的是,细胞内在的DNA传感途径需要 DNA-传感器、cGAS和ER-驻留衔接子、STING的参与,并且是免疫原性的有效诱导剂。 多效性细胞因子家族,I型干扰素(IFN-I)。IFN-I与慢性炎症有关, 自身免疫和癌症等疾病。虽然与年龄相关的慢性炎症的分子成分 炎症仍然不明确,一个重要的机构的工作表明,再循环先天细胞可能是 然而,组织驻留巨噬细胞对衰老的贡献尚未得到解决。 组织巨噬细胞与其他骨髓源性细胞不同,不仅在于它们的起源,还因为 它们整合了表观遗传和微环境的线索,以执行一套独特的功能。除了 随着先天免疫应答的增加,组织巨噬细胞对于组织图案化、解决 炎症和组织修复。在这里,我们提出测试的假设,胞质DNA传感 促进组织巨噬细胞内的组成型IFN-I诱导, 炎症我们将系统地讨论特定的先天过程如何有助于免疫 老年人的功能障碍有三个具体目标。1)我们将评估胞质DNA传感的贡献, 衰老相关的组成性IFN-I和组织中的促炎信号通路 使用缺乏cGAS和STING的小鼠对巨噬细胞进行的细胞毒性试验。2)我们将确定细胞质中 DNA传感途径在通过条件性地改变组织巨噬细胞的命运和功能中的作用 在组织巨噬细胞祖细胞中直接删除STING。作为组织的表观基因组和转录组 巨噬细胞具有高度可塑性,我们将利用下一代测序来识别全基因组变化 随着年龄的增长,这些细胞中的细胞溶质DNA传感途径引起了这种变化。3)最后,我们将扩大我们的 并确定组织巨噬细胞的基线IFN-I特征和反应性 从老年患者的肺部,并将它们与STING的功能丧失单倍型相关联。 通过揭示老年人慢性炎症的分子细节,这项研究的发现提供了 新的免疫调节策略和目标,以加强保护性免疫,并阻止有害的 炎症,如所期望的,在老化过程中。

项目成果

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Shruti Sharma其他文献

Shruti Sharma的其他文献

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{{ truncateString('Shruti Sharma', 18)}}的其他基金

Cytosolic DNA sensing instructs resident macrophage vitality and organismal longevity
胞质 DNA 传感指示常驻巨噬细胞活力和生物体寿命
  • 批准号:
    10901044
  • 财政年份:
    2023
  • 资助金额:
    $ 41.65万
  • 项目类别:
Intracellular nucleic acid sensing and age-related chronic inflammation
细胞内核酸传感与年龄相关的慢性炎症
  • 批准号:
    10551296
  • 财政年份:
    2019
  • 资助金额:
    $ 41.65万
  • 项目类别:
Targeting Interleukin-6 Trans-signaling in Diabetic Retinopathy
靶向白细胞介素 6 反式信号转导治疗糖尿病视网膜病变
  • 批准号:
    9329421
  • 财政年份:
    2016
  • 资助金额:
    $ 41.65万
  • 项目类别:
Targeting Interleukin-6 Trans-signaling in Diabetic Retinopathy
靶向白细胞介素 6 反式信号转导治疗糖尿病视网膜病变
  • 批准号:
    9157948
  • 财政年份:
    2016
  • 资助金额:
    $ 41.65万
  • 项目类别:

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