Mitochondrial-encoded immunity in restoring macrophage homeostasis under age-related metabolic stress

线粒体编码免疫在年龄相关代谢应激下恢复巨噬细胞稳态

• 批准号: 10680230
• 负责人: Michelle C Rice
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680230
• 关键词: Acceleration; Adipose tissue; Age; Aging; Anti-Inflammatory Agents; Atherosclerosis; Biological Assay; Biological Response Modifiers; Bone Marrow; Cardiovascular Diseases; Cell Death; Cell Nucleus; Cells; Cholesterol; Chronic; Circulation; Data; Diabetes Mellitus; Diet; Disease; Disease Progression; Energy-Generating Resources; Environment; Exhibits; Exposure to; Fatty Liver; Fibrosis; Foam Cells; Gene Expression; Gene Expression Profile; Genome; Hepatic; Heterogeneity; High Fat Diet; Homeostasis; Immune; Immune System Diseases; Immune response; Immune signaling; Immunity; Immunomodulators; Impairment; Inflammation; Inflammatory; Innate Immune System; LDL Cholesterol Lipoproteins; Lipids; Liver; Macrophage; Metabolic; Metabolic dysfunction; Metabolic stress; Mitochondria; Mitochondrial DNA; Monitor; Mus; Nonesterified Fatty Acids; Nuclear; Open Reading Frames; Organelles; Output; Overnutrition; Peptide Initiation Factors; Peptides; Peritoneal Macrophages; Phenotype; Play; Process; Production; Property; RNA, ribosomal, 12S; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Signal Transduction; Sterility; Stress; Testing; Therapeutic; Tissues; Triglycerides; age related; aged; aging nutrition; biological adaptation to stress; chronic inflammatory disease; cytokine; diet-induced obesity; experimental study; immune function; inflammatory marker; intraperitoneal; lipid metabolism; lipidomics; mitochondrial genome; monocyte; nonalcoholic steatohepatitis; oxidized low density lipoprotein; prevent; programs; protective effect; recruit; response; single-cell RNA sequencing; transcriptome; wound healing

PROJECT SUMMARY Age-dependent metabolic dysfunction is associated with maladaptive immune responses. Mitochondria are key metabolic organelles that are also capable of activating innate immune signaling. Components of the mitochondria, such as mitochondrial DNA (mtDNA) itself, can trigger immune responses; however, there are currently no known immunomodulators encoded in the mitochondrial genome. MOTS-c is a peptide encoded in the mitochondrial genome that we previously characterized as a regulator of metabolic homeostasis during aging. MOTS-c treatment increases lipid metabolism and prevents diet-induced obesity, fatty liver, and age- dependent physical decline in mice. Our preliminary data indicate that MOTS-c is induced during monocyte activation and translocates to the nucleus to regulate gene expression and reprogram the differentiation of monocytes into macrophages. This suggests that MOTS-c has a crucial role in regulating immune function. Because MOTS-c regulates responses to metabolic stress and modulates macrophage phenotype, I hypothesize that MOTS-c will enhance the adaptive capacity of macrophages to maintain homeostasis during age-related lipid stress. During age- and diet-induced metabolic dysregulation, total cholesterol and triglyceride levels increase in tissue and in circulation. These lipids can induce maladaptive responses in monocyte-derived macrophages that promote chronic sterile inflammation. Here, I will test 1) the role of MOTS- c in preventing maladaptive reprogramming of monocyte-derived macrophages differentiated with lipid stress, and 2) whether MOTS-c treatment in aged and high-fat diet fed mice prevents macrophage maladaptation and tissue damage in the liver associated with chronic inflammation. Collectively, these experiments will test the paradigm-shifting concept that immunity is encoded in both of our co-evolved mitonuclear genomes. This research, if successful, has broad therapeutic applications in the treatment of age-related chronic inflammatory diseases.

项目摘要 依赖年龄的代谢功能障碍与适应不良的免疫反应有关。线粒体是关键 还能够激活先天免疫信号传导的代谢细胞器。组件 线粒体（例如线粒体DNA（mtDNA）本身）可以触发免疫反应。但是，有 目前尚未在线粒体基因组中编码的已知免疫调节剂。 MOTS-C是编码的肽 我们以前以代谢稳态的调节剂的线粒体基因组在 老化。 MOTS-C治疗会增加脂质代谢，并防止饮食诱导的肥胖症，脂肪肝和年龄 - 小鼠的身体下降。我们的初步数据表明在单核细胞中诱导MOTS-C 激活并易位到细胞核以调节基因表达并重新编程 单核细胞成巨噬细胞。这表明MOTS-C在调节免疫功能中具有至关重要的作用。 由于MOTS-C调节对代谢应激的反应并调节巨噬细胞表型，因此 假设MOTS-C将增强巨噬细胞的适应能力以维持体内平衡 在与年龄有关的脂质胁迫期间。在年龄和饮食引起的代谢失调，总胆固醇和 甘油三酸酯水平在组织和循环中增加。这些脂质可以在 单核细胞衍生的巨噬细胞促进慢性无菌炎症。在这里，我将测试1）Mots的作用 - c防止与脂质应激区分单核细胞衍生的巨噬细胞的不良适应性重编程， 2）MOTS-C治疗是否在老年和高脂饮食中喂养小鼠可防止巨噬细胞疾病和 与慢性炎症有关的肝脏的组织损伤。总的来说，这些实验将测试 范式转移概念，即在我们共同进化的有线核基因组中编码免疫力。这 如果成功的话，研究在治疗与年龄有关的慢性炎症方面具有广泛的治疗应用 疾病。