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

描述（由申请人提供）：感官知觉在维持能量平衡和正常体脂含量方面起着重要作用。尽管它的意义，有一个重大的差距，在我们的理解的分子机制，连接特定的感觉方式，在大脑中的能量平衡电路。我们的长期目标是确定将神经系统中的感觉信号与内在线索整合以调节体脂的分子机制，以及导致肥胖的这一过程中的缺陷。这项研究的目的是确定G蛋白GPA-8在C. elegans，一个强大的和易处理的模型系统的能量平衡电路的研究。GPA-8与哺乳动物的蛋白同源，并在C.优雅这项研究的中心假设是，来自感觉神经元的GPA-8信号将氧传感与体脂含量整合在一起。我们希望通过对GPA-8在C.秀丽线虫将是识别神经回路的关键一步， 神经系统中的氧感觉影响身体脂肪含量的保守分子机制。我们的具体目标是：一。识别调节体脂的GPA-8表达神经元。使用神经元特异性启动子，我们将恢复GPA-8突变动物神经元亚群中GPA-8的表达，以确定GPA-8调节体脂作用的精确解剖部位。二.定义GPA-8的细胞内作用模式。GPA-8是一种G蛋白，这表明氧敏感神经元中G蛋白信号的丢失可以调节体脂。我们将测试G蛋白激活周期基因丢失对氧敏感神经元的影响，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。我们将测试参与cGMP信号传导和氧传感的候选遗传途径，以在不同的氧浓度下改变体脂，描绘氧传感和体脂含量整合的神经机制。关于预期成果，拟议工作的完成将使人们能够首次深入了解神经系统中连接氧传感的神经回路和分子机制，以及身体脂肪含量。重要的是，我们的发现将使我们能够识别控制能量平衡的肠-脑轴的信号模式。由于所有正在研究的基因都有明确的哺乳动物直系同源基因，我们在这里的贡献将对快速确定对抗肥胖及其相关疾病的新分子靶点产生积极影响。这项研究意义重大，因为神经氧传感和体脂含量之间的分子联系为我们理解生物体能量平衡和肥胖的潜在原因提供了新的维度。

DESCRIPTION (provided by applicant): 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 molecula 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 of the 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.