LIPID SIGNALING IN REGULATION OF LONGEVITY

调节寿命的脂质信号

• 批准号: 8712311
• 负责人: Meng Carla Wang
• 金额: $ 32.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712311
• 关键词: Acid Lipase; Acyl Coenzyme A; Address; Adipose tissue; Affect; Age; Aging; Aging-Related Process; Agonist; Animals; Biochemical; Bioenergetics; Biological; Biological Assay; Caenorhabditis elegans; Caloric Restriction; Cell membrane; Cells; Cellular Structures; Chemicals; Coenzyme A Ligases; Complex; Consumption; Coupled; Development; Diabetes Mellitus; Disease; Elderly; Electron Transport; Endocrine; Energy Metabolism; Family; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Genes; Genetic; Health; Homeostasis; Homologous Gene; Human; Imaging Techniques; Incidence; Insulin; Insulin-Like Growth Factor I; Invertebrates; Label; Life; Lipase; Lipids; Lipolysis; Longevity; Longevity Pathway; Luciferases; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Molecular Chaperones; Neurodegenerative Disorders; Nuclear; Nuclear Hormone Receptors; Organism; Peroxisome Proliferator-Activated Receptors; Play; Public Health; Regulation; Regulator Genes; Reporter; Role; Signal Transduction; Site; Stem cells; Testing; Tissues; Transcriptional Activation; Transgenic Animals; Transgenic Organisms; Up-Regulation; base; design; fatty acid metabolism; fatty acid oxidation; fatty acid-binding proteins; improved; insight; lipid metabolism; metabolomics; new therapeutic target; novel; oleoylethanolamide; overexpression; oxidation; response

DESCRIPTION (provided by applicant): Lipid metabolism plays a key role in human health and longevity. Lipid metabolism undergoes fundamental changes during aging, which attributes to the development of many age-associated diseases, such as diabetes mellitus, neurodegenerative disorder and cancer. As a major site of lipid metabolism, adipose tissue exerts crucial endocrine effects on the aging process in both invertebrate and vertebrate organisms. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Lipids are not only crucial biological molecules for cellular structure and energy consumption, but also signaling messengers actively involved in transcriptional response and signal transduction. A family of fatty acid binding proteins has been identified as chaperones of lipid messengers to facilitate their cellular effects. Lipase-induced lipolysis is a canonical metabolic process to break down fat, which is recently shown to produce lipid messengers that are essential for the regulation of energy metabolism. During the preliminary studies, we characterized LIPL-4 as a lysosomal acid lipase in Caenorhabditis elegans. Its constitute expression in the fat storage tissue induces lipolysis as well as prolongs organism lifespan, which requires the activity of nuclear hormone receptor NHR- 49 signaling. Furthermore, a lipophilic metabolite oleoylethanolamide (OEA) and a fatty acid binding protein LBP-8 were identified that play crucial roles in the regulation of the LIPL-4-mediated longevity. These studie suggest a novel longevity mechanism that lipase-induced lipolysis promotes longevity via activating specific lipid messengers and lipid signaling. This proposal seeks to dissect the novel functions of lipase-induced lipolysis in the regulation of longevity through the following specific aims: 1) characterize the effects of the lipid messenger OEA in the regulation of organism longevity. 2) Study the mechanism by which LBP-8 functions in the lipase-mediated longevity. 3) Investigate cellular bioenergetic changes that are responsible for organism longevity. We will apply cutting- edge high-throughput metabolomics and label-free chemical imaging techniques combining with genetic, biochemical and transcriptional profiling approaches to dissect the molecular mechanisms underlying this new longevity pathway. These studies will yield new insights to the molecular mechanisms by which lipid metabolism affects the aging process, and also provide novel therapeutic targets to improve metabolic health in elderly.

描述（由申请人提供）：脂质代谢在人类健康和寿命中起着关键作用。随着年龄的增长，脂质代谢发生了根本性的变化，导致了许多与年龄相关的疾病，如糖尿病、神经退行性疾病和癌症。脂肪组织作为脂质代谢的主要场所，在无脊椎动物和脊椎动物的衰老过程中发挥着重要的内分泌作用。然而，它仍然知之甚少脂质代谢是如何耦合到寿命控制。脂质不仅是维持细胞结构和能量消耗的重要生物分子，也是参与转录反应和信号转导的重要信号分子。一个脂肪酸结合蛋白家族已被确定为脂质信使的伴侣，以促进其细胞效应。脂肪酶诱导的脂肪分解是一个典型的代谢过程，以打破脂肪，这是最近被证明产生的脂质信使是必不可少的能量代谢的调节。在前期研究中，我们将LIPL-4鉴定为秀丽隐杆线虫中的溶酶体酸性脂肪酶。它在脂肪储存组织中的组成表达可诱导脂肪分解并延长生物体寿命，这需要核激素受体NHR- 49信号传导的活性。此外，亲脂性代谢产物油酰乙醇酰胺（OEA）和脂肪酸结合蛋白LBP-8被确定为在LIPL-4介导的寿命的调节中起关键作用。这些研究表明，脂肪酶诱导的脂肪分解通过激活特定的脂质信使和脂质信号通路促进长寿。本研究旨在通过以下具体目标来剖析脂肪酶诱导的脂解在调节寿命中的新功能：1）表征脂质信使OEA在生物体寿命调节中的作用。2)研究LBP-8在脂肪酶介导的长寿中的作用机制。3)调查负责有机体寿命的细胞生物能量变化。我们将应用尖端的高通量代谢组学和无标记化学成像技术，结合遗传、生物化学和转录谱分析方法，剖析这一新的长寿途径的分子机制。这些研究将为脂质代谢影响衰老过程的分子机制提供新的见解，并为改善老年人的代谢健康提供新的治疗靶点。