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
• 负责人: ARLAN G. RICHARDSON
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9913983
• 关键词: Affect; Age; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Atherosclerosis; Attenuated; Autopsy; Binding; Brain; Cardiovascular Diseases; Cell Death; Cell membrane; Cells; Chronic; Cognition; Cytolysis; Data; Disease; Dwarfism; Elderly; FRAP1 gene; Feedback; Generations; Hand Strength; Human; Immune; Individual; Inflammaging; Inflammasome; Inflammation; Intervention; Knock-out; Knockout Mice; Link; Longevity; MAP Kinase Gene; Malignant Neoplasms; Measures; Mediating; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mus; Necrosis; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathology; Pathway interactions; Pattern; Performance; Pharmacology; Phosphorylation; Phosphotransferases; Play; Population; Production; Protein Kinase; Proteins; RIPK1 gene; RIPK3 gene; Research; Risk Factors; Role; Signal Transduction; Stimulus; TNF gene; Testing; Tissues; Transcription Factor AP-1; Up-Regulation; Veterans; Wild Type Mouse; age effect; age related; anti aging; base; cell type; cytokine; demographics; dietary restriction; frailty; healthspan; improved; inhibitor/antagonist; insulin sensitivity; mortality; mouse model; neuron loss; novel; prevent

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.

慢性低级炎症（炎症）是衰老的标志，是两者的主要危险因素 老年人的发病率和死亡率。 与年龄相关的疾病，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探测 分子机制/途径负责老动物中慢性低级炎症 以及慢性炎症的增加是否是衰老和与衰老有关的疾病的病因。 坏死tostosis是最近鉴定出的编程坏死的通行途径，诱导细胞死亡裂解 细胞，导致死细胞释放与损伤相关的分子模式（潮湿）。 潮湿是有效的炎症诱导者 人类并与个人的炎症水平密切相关 坏死tostosis在慢性低度炎症中起作用，该炎症随着年龄的增长而发生 坏死性会减弱炎症，导致寿命增加，改善健康状态，以及 与年龄相关的病理学降低。 通过靶向受体相互作用蛋白激酶（RIPK）1或2的间隔以阻断/减少凋亡 混合谱系激酶结构域（例如（MLKL）蛋白），这是对坏死性的起源。 AIM1。 细胞患坏死。 RIPK3 +/-，RIPK3 - / - ，MLKL +/-和MLKL - / - MET）或药理学（用Necrostatin-1s治疗RIPK1抑制剂） 在炎症上，我们还将确定在旧小鼠选定组织中经历领口的细胞类型。 基于我们的假设，我们预测那些表现出随着年龄的年龄意志将会在坏死性凋亡中表现出的组织。 显示出促炎细胞因子的产生和减少/阻断坏死性to骨的增加将减少 组织中的炎症为 - 作为循环水平的促炎细胞因子的水平。 AIM2确定随着年龄的增长而增加坏死的途径 介导与坏死性的炎症相关的增加，TNFα，氧化应激和 MTOR信号已被支撑以启动坏死，而TESE途径随着AIM 2的年龄增长而增加。 我们使用特定 对每种途径的抑制剂。 激活三个途径：IKK-NF-κB，MAPK-AP1和AIM 2中的炎症途径。 评估年龄对WT小鼠各种组织中途径激活的影响，并确定 在RIPK3和MLKL敲除小鼠或或或OR中，哪些途径减少了车轮坏死性。 通过死灵抑素1S治疗。 AIM3。 被阻断/减少的野生型小鼠（例如，RIPK3和/ORKL敲除）将进行比较。 将使用鼠标），我们发现AIM 1中的障碍物的障碍。寿命，HealthSpan（例如，活动，rotarod 性能，抓地力，胰岛素敏感性，认知等）以及这些小鼠与年龄相关的病理学将会 根据我们的假设，与WT小鼠相比 衰老如改善的健康状况，降低病理和寿命增加 提供第一个直接的证据，表明死灵刺激引起的炎症直接与衰老有关，并且 慢性低度炎症在衰老和病理和相关疾病的增加中起作用。