G Protein-Mediated Integration of Oxygen Sensing and Energy Balance in C. Elegans

项目总结/摘要 感官知觉在维持能量平衡和正常的身体脂肪含量方面起着重要作用。 尽管其意义重大，但在我们对连接的分子机制的理解方面存在重大差距。 特定的感觉方式，到大脑中的能量平衡回路。我们的长期目标是确定 整合神经系统中的感觉信号与内在线索以调节身体的分子机制 脂肪，以及这个过程中导致肥胖的缺陷。拟议研究的目的是确定 G蛋白GPA-8在C. elegans，一个强大的和易处理的模型系统的研究能源 平衡电路GPA-8与哺乳动物的味蛋白G蛋白同源，并在哺乳动物中表达。 C.优雅这项研究的核心假设是，GPA-8 来自感觉神经元的信号将氧感测与身体脂肪含量整合。我们预计 了解GPA-8在C.这将是确定 神经回路和保守的分子机制， 影响身体脂肪含量。我们的具体目标是：一。确定调节GPA-8的表达神经元 身体脂肪使用神经元特异性启动子，我们将恢复GPA-8中神经元亚群的GPA-8表达。 突变动物来确定GPA-8在调节体脂中作用的精确解剖学位点。二.定义 GPA-8的细胞内作用模式。GPA-8是一种G蛋白，这表明G蛋白信号转导的缺失， 氧传感神经元调节身体脂肪。我们将测试G蛋白激活周期基因缺失的影响， 特别是在氧敏感神经元中，以确定GPA-8的细胞内作用模式。三.确定 氧感觉与脂肪储存的整合机制。我们将测试一个候选基因路径 参与cGMP信号传导和在不同氧下对体脂肪变化的氧传感 浓度，以描绘氧传感和体脂整合的神经机制 内容关于预期成果，完成拟议工作将使人们能够初步了解 进入神经回路和分子机制，连接神经系统中的氧感， 身体脂肪含量重要的是，我们的研究结果将使我们能够识别肠道-大脑的信号模式， 控制能量平衡的轴。因为所有正在研究的基因都有明确的哺乳动物直系同源物，我们的 这方面的贡献将对快速确定对抗肥胖的新分子靶点产生积极影响 及其相关疾病。这项研究之所以重要，是因为 神经氧传感和身体脂肪含量为我们理解生物体提供了一个新的维度。 能量平衡和肥胖的根本原因。

PROJECT SUMMARY/ABSTRACT Sensory perception plays an important role in maintaining energy balance and normal body fat content. Despite its significance, there is a major gap in our understanding of the molecular mechanisms that link specific sensory modalities, to energy balance circuits in the brain. Our long-term goal is to identify the molecular mechanisms that integrate sensory signals in the nervous system with intrinsic cues to regulate body fat, and the defects in this process that lead to obesity. The objective the of proposed research is to determine the role of the G¿ protein GPA-8 in C. elegans, a powerful and tractable model system for the study of energy balance circuits. GPA-8 is homologous to the mammalian ¿-gustducin G¿ protein, and is expressed in oxygen-sensing neurons in C. elegans. The central hypothesis of the proposed research is that GPA-8 signaling from sensory neurons integrates oxygen sensing with body fat content. We expect that understanding the mechanism of action of GPA-8 in C. elegans will be a critical step toward identifying the neural circuits and conserved molecular mechanisms by which oxygen sensation in the nervous system influences body fat content. Our Specific Aims are to: I. Identify the GPA-8-expressing neurons that regulate body fat. Using neuron-specific promoters, we will restore GPA-8 expression in subsets of neurons in gpa-8 mutant animals to define the precise anatomical sites of GPA-8 action in regulating body fat. II. Define the intracellular mode of action for GPA-8. GPA-8 is a G¿ protein suggesting that loss of G protein signaling in oxygen-sensing neurons regulates body fat. We will test the effects of loss of G protein activation cycle genes specifically in oxygen-sensing neurons, to determine the intracellular mode of action of GPA-8. III. Determine the mechanisms of integration of oxygen sensation with fat stores. We will test a candidate genetic pathway involved in cGMP signaling and in oxygen-sensing for changes in body fat under different oxygen concentrations, to delineate the neural mechanisms underlying the integration of oxygen-sensing and body fat content. With respect to expected outcomes, the completion of the proposed work will enable the first insights into the neural circuits and molecular mechanisms that connect oxygen-sensing in the nervous system, with body fat content. Importantly, our findings will allow us to identify signaling paradigms underlying the gut-brain axis that controls energy balance. Because all of the genes under study have clear mammalian orthologs, our contribution here will have a positive impact on rapidly identifying new molecular targets for combating obesity and its associated illnesses. The proposed research is significant because a molecular connection between neural oxygen sensing and body fat content provides a new dimension to our understanding of organismal energy balance and the causes underlying obesity.