Senescent cells drive mt-DNA accumulation and inflamm-aging

衰老细胞驱动 mt-DNA 积累和炎症衰老

• 批准号: 10515843
• 负责人: Stefan Gunther Tullius
• 金额: $ 50.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515843
• 关键词: Acute; Address; Affect; Age; Aging; Allografting; Animal Model; Animals; Anti-Inflammatory Agents; Area; Automobile Driving; BAX gene; Cell Aging; Cells; Chronic; Clinical; Clinical Research; Collection; Communication; DNA; Data; Dendritic Cells; Dendritic cell activation; Dialysis procedure; Disease; Experimental Models; Goals; Graft Survival; Health; Human; Immune response; Immunocompetence; Impairment; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-17; Kinetics; Ligands; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morbidity - disease rate; Mus; Nitrogen; Older Population; Organ; Organ Donor; Organ Transplantation; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Patients; Pattern; Play; Population; Process; Public Health; Reperfusion Injury; Research; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Source; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Transplantation; Waiting Lists; age related; aging population; clinically relevant; clinically significant; cytokine; end-stage organ failure; experience; experimental study; immunogenicity; improved; injury and repair; isoimmunity; mortality; novel; older patient; organ injury; organ transplant recipient; permease; pre-clinical; preclinical study; preservation; receptor; repaired; response; senescence; treatment choice

Project Summary The aging population is on the rise. By 2030, for the first time, both the population older than 65 and those younger than 18 years will contribute equally with 21% to the overall US population. Organ transplantation is hampered by a limited supply of organs with many patients waiting for numerous years and numerous patients dying before getting a transplant. Organs from older donors are available, however, frequently not considered or discarded with concerns of compromised function and augmented immunogenicity. We have previously documented the impact of aging in clinical transplantation and have dissected some of the mechanisms that drive the augmented immunogenicity of older organs. We have identified old intragraft dendritic cells (DC) as drivers of an IL-17-driven immune response. Mechanisms that activate old DCs, however, remain to be determined. In additional preliminary data, we have now documented a systemic increase of cell- free mitochondrial DNA (cf-mt-DNA), a damage-associated molecular pattern (DAMP) that accumulates in aging. Notably, blocking TLR-9, the ligand for mt-DNA, reduced the immunogenicity of old DCs and prolonged the survival of old transplants. Additional preliminary data documented a compromised clearance of senescent cells in older mice. Senolytics, agents that deplete senescence cells reduced inflammatory responses associated with ischemia-reperfusion injury (IRI) in an age-dependent fashion. In specific aim 1, we will therefore define the impact of aging on DAMP release and delineate whether the transplantation of old organs can promote inflammation via the dissemination of senescent cells. Our preliminary experiments have also shown that the communication between DCs and T cells is impacted by aging. In specific aim 2, we will therefore elucidate the underlying mechanisms that promote mtDNA release and inflamm-aging. Here, we will test the role of nitrogen permease regulator-like 3 (NLRP3) and will assess whether elevated DAMP levels mediate inflammation via this signaling pathway in an age dependent manner. We have also accumulated preliminary data showing that senolytics reduced mtDNA levels while ameliorating DC and T-cell activation in an age-specific fashion. Additional preliminary data have also shown that a single application of senolytics in older donor animals prolonged transplant survival. We thus submit that senolytics will have the capacity to improve organ quality and reduce the augmented immunogenicity in aging. In specific aim 3, we will therefore dissect the translational capacity of senolytics administered to donors, recipients, or as an addition to the preservation solution. We believe that our proposal is built on a strong collection of preliminary data, the availability of unique experimental models and the support of a distinctive group of researchers. We are thus confident that our proposal will contribute substantially to an improved understanding in an area of unmet need.

项目摘要 人口老龄化正在上升。到2030年，这是第一次，年龄在65岁以上和 18岁以下的年轻人将对美国总人口贡献21％。 器官供应有限的器官受到阻碍，许多患者正在等待许多患者 年份和许多患者在接受移植之前死亡。但是，有来自年长捐赠者的器官 经常不考虑受损功能和增强免疫原性的担忧。 我们以前已经记录了衰老在临床移植中的影响，并剖析了一些 驱动旧器官增强免疫原性的机制。我们已经确定了旧的内部 树突状细胞（DC）是IL-17驱动的免疫反应的驱动因素。但是，激活旧DC的机制 仍有待确定。在其他初步数据中，我们现在已经记录了细胞的系统性增加 游离线粒体DNA（CF-MT-DNA），这是一种与损伤相关的分子模式（湿），可在衰老中积累。 值得注意的是，阻止TLR-9，MT-DNA的配体，降低了旧DC的免疫原性并延长了 旧移植的生存。其他初步数据记录了对衰老细胞的被损害的清除率 在老鼠中。鼻孔剂，耗尽衰老细胞的药物降低了与 以年龄的方式进行缺血 - 重新灌注损伤（IRI）。在特定目标1中，我们将定义 衰老对潮湿释放的影响并描述旧器官的移植是否可以促进 通过传播衰老细胞的炎症。我们的初步实验也表明 DC和T细胞之间的通信受到衰老的影响。在特定目标2中，我们将阐明 促进mtDNA释放和炎症的基本机制。在这里，我们将测试氮的作用 渗透酶调节剂样3（NLRP3），并将评估较高的潮湿水平是否通过此介导炎症 信号通路以年龄的依赖方式。我们还积累了初步数据，表明 塞溶剂剂降低了mtDNA水平，同时以年龄为特定的方式改善直流和T细胞激活。 其他初步数据还表明，在老年供体动物中使用单溶剂的单一应用 长时间的移植生存。因此，我们认为Senolotics将有能力提高器官质量和 降低衰老中的免疫原性。在特定目标3中，我们将剖析翻译 给捐助者，接受者或作为保存解决方案的补充的鼻孔术的能力。 我们认为，我们的建议建立在大量的初步数据基础上，可用性 实验模型和独特的研究人员的支持。因此，我们相信我们的 提案将在未满足需求的领域有了改善的理解做出重大贡献。