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 依赖性代谢功能障碍与适应不良的免疫反应有关。线粒体是关键 代谢细胞器，也能够激活先天免疫信号。的部件 线粒体，如线粒体DNA（mtDNA）本身，可以触发免疫反应;然而， 目前还没有已知的免疫调节剂在线粒体基因组中编码。MOTS-c是一种编码于 我们之前将线粒体基因组描述为代谢稳态的调节剂， 衰老MOTS-c治疗可增加脂质代谢，预防饮食诱导的肥胖、脂肪肝和衰老。 小鼠的依赖性体力下降。我们的初步数据表明，MOTS-c在单核细胞 激活并转移到细胞核以调节基因表达并重新编程细胞的分化。 单核细胞转化为巨噬细胞。这表明MOTS-c在调节免疫功能中具有关键作用。 由于MOTS-c调节对代谢应激的反应并调节巨噬细胞表型， 假设MOTS-c将增强巨噬细胞维持内环境稳定适应能力 与年龄有关的脂质压力。在年龄和饮食诱导的代谢失调期间，总胆固醇和 组织和循环中的甘油三酯水平增加。这些脂质可以诱导适应不良反应， 单核细胞衍生的巨噬细胞，促进慢性无菌性炎症。在这里，我将测试1）MOTS的作用- c在防止由脂质应激分化的单核细胞衍生的巨噬细胞的适应不良重编程中， 和2）MOTS-c治疗老年和高脂肪饮食喂养的小鼠是否防止巨噬细胞适应不良， 与慢性炎症相关的肝脏组织损伤。总的来说，这些实验将测试 我们共同进化的线粒体基因组中编码了免疫力这一范式转变的概念。这 研究如果成功，在治疗与年龄相关的慢性炎症方面具有广泛的治疗应用。 疾病