Genetics of Cell Signaling in C. elegans Growth Regulation

描述(由申请人提供)：生长是生物系统的一个基本属性，必须进行严格的调控，以确保正常的生物功能。对生长的错误调控导致了各种疾病和残疾，最明显的是肥胖和癌症，在这些疾病中，细胞过度生长和/或细胞增殖。由于生长控制的根本性质，其核心调控逻辑可能会通过进化得到保守，从而能够使用简单的、遗传上易处理的生物作为模型系统。我们已经确定DBL-1(与BMP2相关的转化生长因子超家族的一个配体)是线虫体内身体大小的主要调节因子。为了阐明DBL-1调控生长的分子机制，我们鉴定了DBL-1转录靶基因，发现这些靶基因包括胰岛素生长因子和脂肪代谢调节因子。这些初步数据为研究胰岛素和转化生长因子信号之间的串扰及其与生长控制的相关性提供了框架。我们假设DBL-1部分通过下调胰岛素途径，导致脂肪代谢和细胞生长的变化来调节生长。为了验证我们的假设，我们将解决以下问题：(1)DBL-1是否调节脂肪代谢？以及(2)DBL-1和胰岛素信号是如何整合来决定机体大小的？通过完成这个项目的目标，我们将揭示体内胰岛素和转化生长因子信号之间的调控相互作用及其对脂肪积累和生长的影响。我们的工作将为这两条高度保守的信号通路之间的整合和串扰机制提供有价值的信息，为可能干预人类生长相关疾病提供基础。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方面的最新技术，以及口头和书面交流技能。 公共卫生相关性：发育障碍是美国面临的一个主要公共卫生威胁。在这些疾病中，癌症和肥胖症的发病率惊人地高。这项工作将利用一个简单的模式生物的优势来揭示潜在的生长调节的遗传和细胞机制，并期望为这些疾病的未来治疗确定潜在的靶点。

DESCRIPTION (provided by applicant): Growth is a fundamental property of biological systems that must be exquisitely well regulated to ensure normal organismal function. The misregulation of growth contributes to a variety of diseases and disabilities, most notably obesity and cancer in which excessive cell growth and/or cell proliferation occur. Because of the fundamental nature of growth control, its core regulatory logic is likely to be conserved through evolution, enabling the use of simple, genetically tractable organisms as model systems. We have identified DBL-1 (a ligand of the TGF¿ superfamily related to BMP2) as a major regulator of body size in the nematode C. elegans. To elucidate the molecular mechanisms by which DBL-1 regulates growth, we have identified DBL-1 transcriptional target genes and found that these target genes include insulin growth factors and regulators of fat metabolism. These preliminary data provide the framework for an investigation into the crosstalk between insulin and TGF¿ signaling and its relevance to growth control. We hypothesize that DBL-1 regulates growth in part by downregulation of the insulin pathway leading to changes in fat metabolism and cell growth. To test our hypothesis, we will address the following questions: (1) Does DBL-1 regulate fat metabolism?; and (2) How are DBL-1 and insulin signaling integrated to determine organismal size? By accomplishing the aims of this project, we will uncover the regulatory interactions between insulin and TGF¿ signaling in vivo and their consequences for fat accumulation and growth. Our work will provide valuable information on the mechanisms of integration and crosstalk between these two highly conserved signaling pathways, providing the basis for possible intervention into growth-related disorders 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. PUBLIC HEALTH RELEVANCE: Disorders of growth pose a major public health threat facing the United States. Among these disorders, incidences of cancer and of obesity are strikingly high. This work will exploit the advantages of a simple model organism to uncover the genetic and cellular mechanisms underlying growth regulation, with the expectation of identifying potential targets for future therapies for these diseases.