Investigating the Role of PLIN2 in Senescence

研究 PLIN2 在衰老中的作用

• 批准号: 10669556
• 负责人: Mahima Devarajan
• 金额: $ 4.14万
• 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/10669556
• 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; 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; chemokine; cyclooxygenase 2; cytokine; experimental study; healthspan; inflammatory modulation; 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.

项目摘要/摘要 随着全球人口的增长，了解衰老相关疾病的生物学基础变得至关重要 年龄和慢性病的负担给医疗系统带来了压力。细胞衰老已经成为一种 多种与年龄相关的病理的统一特征，已被确定为 多种癌症、神经退行性疾病、肝纤维化和脂肪变性以及与年龄相关的肌肉 功能障碍。衰老是细胞周期停滞的一种状态，其特征还包括线粒体功能障碍、脂质 积聚和高度炎症性衰老相关分泌表型(SASP)。此SASP是 目前被认为是衰老相关组织功能障碍的主要原因之一。SASP， 由细胞因子/趋化因子、生长因子、蛋白酶和脂源性二十烷类化合物组成，促进慢性 邻近细胞的炎症和功能障碍。到目前为止，这方面的研究主要集中在 分泌的SASP蛋白的有害影响，留下脂质/二十烷类对SASP和 衰老在很大程度上没有被研究过。 衰老细胞的特征是积累脂滴(LDs)，这是最近被发现的中枢 炎症反应中的结节和二十烷类化合物的产生场所。LD的新陈代谢可以帮助 根据驻留在LD表面的蛋白质的组成来预防或预防炎症。一 这种蛋白质，Perilipin 2(PLIN2)，已被证明在多种炎症条件和 可调节炎性脂类从LD流出。我的主要目标是阐明 LDS和LD蛋白通过这种方式调节衰老，这可能允许这种炎症的特定靶点 进程。我的中心假设是PLIN2在SASP的启动和维持中起关键作用 和衰老。我们将通过建立PLIN2与之相互作用的机制来检验这一假设 二十烷类化合物在衰老中的合成酶，并调节二十烷类化合物从LD的释放。那我们就会 研究表明，在衰老小鼠的衰老细胞中敲除PLIN2可以减轻全局炎症，减少SASP在衰老小鼠中的表达 促进衰老细胞，提高衰老小鼠的健康寿命。到目前为止，还没有研究调查PLIN2在 衰老。这项提议将为建立PLIN2和LD作为衰老和 SASP，从而揭示了衰老促进衰老的新机制。