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

G 蛋白介导的线虫氧传感和能量平衡整合

• 批准号: 9020225
• 负责人: Supriya Srinivasan
• 金额: $ 41.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020225
• 关键词: Afferent Neurons; American; Animals; Biological Models; Blood Circulation; Body fat; Brain; Brain region; Caenorhabditis elegans; Couples; Cues; Cyclic GMP; Data; Defect; Diabetes Mellitus; Dimensions; Esthesia; Event; Fatty acid glycerol esters; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Goals; Health; Heart Diseases; Human; Inflammation; International; Knowledge; Laboratories; Lead; Life; Link; Lipase; Malignant Neoplasms; Measures; Mediating; Metabolic; Modality; Modeling; Molecular; Molecular Target; Mus; Nervous system structure; Neurons; Neurosecretory Systems; Nutrient; Obesity; Orthologous Gene; Outcome; Output; Oxygen; Pathway interactions; Perception; Physiological; Play; Positioning Attribute; Process; Protein Family; Public Health; Regulation; Reporter; Research; Role; Sensory; Sequence Homology; Signal Transduction; Site; Testing; Tissues; Transcriptional Activation; Ursidae Family; Work; base; behavioral response; combat; detection of nutrient; energy balance; insight; member; mutant; neural circuit; neuromechanism; neuroregulation; novel; promoter; protein activation; rat Gnat3 protein; receptor-mediated signaling; relating to nervous system; research study

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.

描述（适用提供）：感官感知在维持能量平衡和正常体内脂肪含量方面起着重要作用。尽管它具有重要意义，但我们对将特定感觉方式的分子机制与大脑平衡电路保持联系的分子机制存在重大差距。我们的长期目标是确定具有内在提示以调节体内脂肪的神经系统中的感觉信号的分子机制，以及导致肥胖的过程中的缺陷。拟议的研究的目的是确定G蛋白GPA-8在秀丽隐杆线虫中的作用，秀丽隐杆线虫是一种强大且可操作的模型系统，用于研究能量平衡电路。 GPA-8与哺乳动物gustducing¿蛋白是同源的，并且在秀丽隐杆线虫的氧气神经元中表达。拟议研究的中心假设是，来自感觉神经元的GPA-8信号传导将氧气感应与体内脂肪含量相结合。我们预计了解秀丽隐杆线中GPA-8的作用机理将是确定神经元和的关键一步 神经系统中氧气的保守分子机制会影响体内脂肪含量。我们的具体目的是：I。确定调节体内脂肪的表达GPA-8的神经元。使用神经元特异性启动子，我们将恢复GPA-8突变动物中神经元子集中的GPA-8表达，以定义调节体脂肪中GPA-8作用的精确解剖位点。 ii。定义GPA-8的细胞内作用方式。 GPA-8是一种G蛋白，表明GPA-8在氧气敏感神经元中的G蛋白信号传导损失可调节体内脂肪。我们将测试特定于氧气神经元中G蛋白激活周期基因丧失的影响，以确定GPA-8的细胞内作用方式。 iii。确定氧气与脂肪储存的整合的机制。我们将测试参与CGMP信号传导和氧气感应的候选遗传途径，以在不同的氧气浓度下体内脂肪的变化，以描述氧气和体内脂肪含量整合的神经元机制。关于预期的结果，提议的工作的完成将使您能够对神经元电路和分子机制进行最初的见解，这些机制将神经系统中的氧气连接到体内脂肪含量。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道轴的信号范例。由于研究的所有基因都有明显的哺乳动物直系同源物，因此我们在这里的贡献将对快速识别打击肥胖及其相关疾病的新分子靶标有积极影响。拟议的研究很重要，因为神经氧敏感性和体内脂肪含量之间的分子联系为我们对有机能量平衡的理解和根本肥胖的原因提供了一个新的维度。