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

 描述（由申请人提供）：肥胖和代谢紊乱患病率的增加构成了美国面临的主要公共卫生威胁。新出现的证据鉴定了转化生长因子β（TGF β）超家族，其包括TGF β s、激活素/活化素和骨形态发生蛋白（BMP），作为肥胖和代谢紊乱的参与者和可能的治疗靶点。例如，在人类中，TGF β 1、β 2受体和受体BMPR 1A的表达水平与肥胖正相关。此外，TGF β超家族成员调节肥胖，以及胰岛素基因转录和胰岛素分泌。我们的研究表明，C。秀丽线虫BMP同源物DBL-1类似地调节胰岛素基因转录和脂肪积累。梭elegans系统为哺乳动物能量平衡和脂肪代谢的研究提供了一种补充方法，因为基本的生化和遗传机制是相同的。有大量的工具可用于操作和分析C。包括突变体、转基因、dsRNA干扰（RNAi）和活体成像技术。值得注意的是，这些方法允许在其自然生理环境中分析体内的细胞和生化功能。因此，我们拥有必要的工具和初步数据来阐明BMP途径影响代谢稳态的细胞、遗传和生化机制。该提案的目标是确定DBL-1在分子，细胞和生物体水平上调节脂肪代谢的机制。我们假设DBL-1促进合成代谢状态，部分通过下调胰岛素/IGF-1样信号（IIS）。我们将解决以下问题来验证我们的假设：（1）DBL-1/BMP通过哪些调控节点调节脂肪组成和积累？(2)DBL-1途径在调节脂肪代谢中的细胞作用部位是什么？(3)DBL-1调节脂肪代谢是否由IIS途径介导？在资助期结束时，我们希望能够阐明DBL-1/BMP信号调节脂肪积累的机制，它介导这种功能的组织，以及DBL-1/BMP途径依赖于IIS途径的程度。这项工作将确定这些过程之间最具生物学相关性的联系，为更好地了解人类肥胖的风险因素和潜在治疗靶点提供基础。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学习分子生物学和显微镜的当前技术以及口头和书面沟通技巧。

 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.