Regulation of Metabolism by C. Elegans DBL-1/BMP Signaling

线虫 DBL-1/BMP 信号传导对代谢的调节

• 批准号: 8957493
• 负责人: CATHY SAVAGE-DUNN
• 金额: $ 36.96万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957493
• 关键词: Activins; Address; Animal Model; BMPR1A gene; Biochemical; Biochemical Genetics; Biological; Biological Assay; Body Size; Bone Morphogenetic Proteins; Caenorhabditis elegans; Cardiovascular Diseases; Cells; Communication; Data; Diabetes Mellitus; Disease; Double-Stranded RNA; Down-Regulation; Energy Metabolism; Ensure; Epidemic; Family; Fatty acid glycerol esters; Foundations; Genetic; Genetic Transcription; Goals; Grant; Growth; Growth Factor; Health; Health Care Costs; Homeostasis; Homologous Protein; Human; Imaging Techniques; Incidence; Inherited; Insulin; Insulin-Like Growth Factor I; Learning; Life; Ligands; Link; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microscopy; Molecular; Molecular Biology; Molecular Genetics; Obesity; Oral; Overweight; Participant; Pathway interactions; Physiological; Prevalence; Process; Public Health; Quality of life; RNA Interference; Regulation; Research; Risk; Risk Factors; Signal Pathway; Signal Transduction; Site; System; Techniques; Testing; Tissues; Training; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Organisms; United States; Work; Writing; bone morphogenetic protein receptors; graduate student; in vivo; inhibin; inhibin receptor; insulin secretion; lipid metabolism; loss of function; meetings; member; molecular imaging; mortality; mutant; procollagen C-endopeptidase; prototype; public health relevance; skills; symposium; therapeutic target; tool; undergraduate student

 DESCRIPTION (provided by applicant): The increasing prevalence of obesity and metabolic disorders pose a major public health threat facing the United States. Emerging evidence identifies the Transforming Growth Factor ß (TGFß) superfamily, which includes TGFßs, activins/inhibins, and bone morphogenetic proteins (BMPs), as a participant in and a possible therapeutic target for obesity and metabolic disorders. For example, in humans, expression levels of TGFß, inhibins, and the receptor BMPR1A are positively correlated with obesity. Furthermore, TGFß superfamily members regulate adiposity, as well as insulin gene transcription and insulin secretion. Our studies have revealed that the C. elegans BMP homolog, DBL-1, similarly regulates insulin gene transcription and fat accumulation. The C. elegans system provides a complementary approach to mammalian studies on energy homeostasis and fat metabolism, since the fundamental biochemical and genetic mechanisms are the same. A wealth of tools exists for the manipulation and analysis of C. elegans, including mutants, transgenics, dsRNA interference (RNAi), and live imaging techniques. Significantly, these approaches allow for the analysis of cellular and biochemical functions in vivo, in their natural physiological context. Thus, we possess the tools and the preliminary data necessary to elucidate the cellular, genetic, and biochemical mechanisms by which a BMP pathway impinges on metabolic homeostasis. The goal of this proposal is to identify the mechanisms by which DBL-1 regulates fat metabolism at molecular, cellular, and organismal levels. We hypothesize that DBL-1 promotes an anabolic state, in part by downregulation of insulin/IGF-1-like signaling (IIS). We will address the following questions that test our hypothesis: (1) What are the regulatory nodes through which DBL-1/BMP modulates fat composition and accumulation? (2) What is the cellular site of action of the DBL-1 pathway in regulation of fat metabolism? (3) Is DBL-1 regulation of fat metabolism mediated by the IIS pathway? At the completion of the grant period, we expect to have elucidated the mechanisms by which DBL-1/BMP signaling modulates fat accumulation, the tissues in which it mediates this function, and the degree to which the DBL-1/BMP pathway depends on the IIS pathway. This work will identify the most biologically relevant links between these processes, providing the foundation for a better understanding of the risk factors and potential therapeutic targets for obesity in humans. Additionally, this project will provide training opportunities for a graduate student and undergraduate students, who will learn current techniques in molecular biology and microscopy, as well as oral and written communication skills through lab meetings and attendance at professional conferences.

 描述（由适用提供）：肥胖和代谢障碍的越来越流行构成美国面临的重大公共卫生威胁。新兴证据确定了包括TGFß，activins/抑制素和骨形态发生蛋白（BMP）在内的转化生长因子ß（TGFß）超家族，是参与者的肥胖和肥胖和代谢疾病的可能治疗靶标。例如，在人类中，TGFß，抑制剂和受体BMPR1A的表达水平与肥胖呈正相关。此外，TGFß超家族成员调节肥胖，胰岛素基因转录和胰岛素分泌。我们的研究表明，秀丽隐杆线虫BMP同源物DBL-1类似地调节胰岛素基因转录和脂肪积累。秀丽隐杆线虫系统为能量稳态和脂肪代谢的哺乳动物研究提供了一种完整的方法，因为基本的生化和遗传机制是相同的。对于秀丽隐杆线虫的操纵和分析，存在大量工具，包括突变体，转化学，DSRNA干扰（RNAi）和实时成像技术。值得注意的是，这些方法允许在自然物理环境中分析体内细胞和生化功能。这是我们拥有所需的工具和初步数据，以阐明BMP途径会影响代谢稳态的细胞，遗传和生化机制。该建议的目的是确定DBL-1在分子，细胞和有机水平下调节脂肪代谢的机制。我们假设DBL-1促进了合成代谢状态，部分原因是胰岛素/IGF-1样信号（IIS）的下调。我们将解决测试我们假设的以下问题：（1）DBL-1/BMP通过哪些调节节点调节脂肪成分和加速度？ （2）DBL-1途径在调节脂肪代谢中的作用细胞位点是什么？ （3）IIS途径介导的脂肪代谢的DBL-1调节？在赠款期结束时，我们希望阐明DBL-1/BMP信号传导调节脂肪组成的机制，其介导该功能的组织以及DBL-1/BMP途径在IIS途径上依赖于IIS途径的程度。这项工作将确定这些过程之间最相关的联系，为更好地理解人类对象的危险因素和潜在的治疗目标奠定了基础。此外，该项目将为研究生和本科生提供培训机会，他们将通过实验室会议和参加专业会议来学习分子生物学和显微镜的当前技术以及口头和书面交流技能。