Investigating the Role of PLIN2 in Senescence

研究 PLIN2 在衰老中的作用

• 批准号: 10387815
• 负责人: Mahima Devarajan
• 金额: $ 4.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2025-12-24
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387815
• 关键词: Ablation; Affect; Age; Age-Months; Aging; Anabolism; Arachidonic Acids; Area; Attenuated; Automobile Driving; Binding; Biological; Cell Aging; Cell Culture Techniques; Cell Cycle Arrest; Cells; Characteristics; Chronic; Chronic Disease; Data; Disease; Eicosanoid Production; Eicosanoids; Enzymes; Etiology; Excision; Fatty Liver; Functional disorder; Goals; Growth Factor; Healthcare Systems; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Label; Leukotrienes; Lipid Binding; Lipids; Lipoxins; Literature; Liver Fibrosis; Longevity; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modeling; Mus; Muscle; Neurodegenerative Disorders; Obesity; Pathology; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Phospholipase A2; Physicians; Play; Population; Process; Prostaglandins; Proteins; Regulation; Research; Role; Scientist; Signal Transduction; Site; Stimulus; Surface; Testing; Thromboxanes; Tissues; Training; Work; aged; base; chemokine; cyclooxygenase 2; cytokine; experimental study; healthspan; insight; knock-down; lipid metabolism; mitochondrial dysfunction; nonalcoholic steatohepatitis; novel; overexpression; perilipin; phenotypic biomarker; preference; response; senescence

PROJECT SUMMARY/ABSTRACT Understanding the biological basis of aging-related diseases is becoming paramount as the global population ages and the burden of chronic disease weighs on healthcare systems. Cellular senescence has emerged as a unifying feature of multiple age-associated pathologies, having been identified as a significant player in numerous cancers, neurodegenerative diseases, hepatic fibrosis and steatosis, and age associated muscle dysfunction. Senescence is a state of cell cycle arrest that also features mitochondrial dysfunction, lipid accumulation, and a highly inflammatory senescence-associated secretory phenotype (SASP). This SASP is currently thought to be one of the primary causes of senescence-associated tissue dysfunction. The SASP, consisting of cytokines/chemokines, growth factors, proteases, and lipid-derived eicosanoids, promotes chronic inflammation and dysfunction in neighboring cells. To date, research in this area has mainly focused on detrimental effects of secreted SASP proteins, leaving the lipid/eicosanoid contribution to SASP and senescence largely unstudied. Senescent cells characteristically accumulate lipid droplets (LDs), which have recently been identified as central nodes in the inflammatory response and as sites for eicosanoid production. LD metabolism can either contribute to or protect against inflammation depending on the composition of proteins residing on the LD surface. One such protein, Perilipin 2 (PLIN2), has been shown to play pivotal roles in multiple inflammatory conditions and can regulate the efflux of inflammatory lipids from the LD. My primary objective is to elucidate the mechanisms by which LDs and LD proteins modulate senescence, which could allow for specific targeting of this inflammatory process. My central hypothesis is that PLIN2 plays a key role in the initiation and maintenance of SASP and senescence. We will test this hypothesis by establishing a mechanism by which PLIN2 interacts with eicosanoid synthesizing enzymes in senescence and regulates eicosanoid release from the LD. Then we will show that PLIN2 knockout in senescent cells in aged mice attenuates global inflammation, reduces the SASP in senescent cells, and enhances healthspan of aged mice. No study to date has investigated a role for PLIN2 in senescence. This proposal will lay the groundwork establishing PLIN2 and the LD as central to senescence and SASP, thus unveiling a novel mechanism by which senescence contributes to aging.

项目总结/文摘