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: 10188378
• 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/10188378
• 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; Transplant Recipients; 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; 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.

项目概要 人口老龄化正在加剧。到 2030 年，65 岁以上人口和 18 岁以下的人口将占美国总人口的 21%。 器官供应有限，许多患者等待大量器官移植，这阻碍了器官移植 多年来，许多患者在接受移植之前就死亡了。然而，来自老年捐献者的器官是可用的， 由于担心功能受损和免疫原性增强，经常不考虑或丢弃。 我们之前已经记录了衰老对临床移植的影响，并剖析了一些 驱动老年器官免疫原性增强的机制。我们已经识别出旧的移植物 树突状细胞 (DC) 作为 IL-17 驱动的免疫反应的驱动因素。然而，激活旧 DC 的机制， 仍有待确定。在额外的初步数据中，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)，一种在衰老过程中积累的损伤相关分子模式 (DAMP)。 值得注意的是，阻断 TLR-9（mt-DNA 的配体）可降低老 DC 的免疫原性并延长其存活时间。 旧移植物的存活。额外的初步数据记录了衰老细胞的清除受损 在年长的小鼠中。 Senolytics 是一种消耗衰老细胞的药物，可减少与衰老相关的炎症反应 缺血再灌注损伤（IRI）与年龄相关。因此，在具体目标 1 中，我们将定义 衰老对DAMP释放的影响并阐明老年器官移植是否可以促进 通过衰老细胞的传播产生炎症。我们的初步实验还表明 DC 和 T 细胞之间的通讯受到衰老的影响。因此，在具体目标 2 中，我们将阐明 促进 mtDNA 释放和炎症衰老的潜在机制。在这里，我们来测试一下氮气的作用 通透调节因子样 3 (NLRP3)，并将评估 DAMP 水平升高是否通过此介导炎症 信号通路以年龄依赖性方式进行。我们还积累了初步数据表明 senolytics 降低了 mtDNA 水平，同时以特定年龄的方式改善 DC 和 T 细胞的激活。 其他初步数据还表明，在老年供体动物中单次应用 senolytics 延长移植存活率。因此，我们认为 senolytics 将具有改善器官质量和 降低衰老过程中增强的免疫原性。因此，在具体目标 3 中，我们将剖析翻译 senolytics 给予捐赠者、接受者的能力，或作为保存溶液的添加物。 我们相信，我们的建议是建立在大量初步数据收集、独特的可用信息的基础上的 实验模型和一群独特的研究人员的支持。因此，我们有信心我们的 该提案将大大有助于增进对未满足需求领域的了解。