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（由申请人提供）：感官知觉在维持能量平衡和正常身体脂肪含量方面发挥着重要作用。尽管其意义重大，但我们对将特定感觉模式与大脑能量平衡回路联系起来的分子机制的理解存在重大差距。我们的长期目标是确定将神经系统中的感觉信号与调节身体脂肪的内在线索整合起来的分子机制，以及该过程中导致肥胖的缺陷。本研究的目的是确定线虫中 G¿ 蛋白 GPA-8 的作用，线虫是一个强大且易于处理的模型系统，用于研究能量平衡回路。 GPA-8 与哺乳动物的“-gustducin G”蛋白同源，在线虫的氧敏感神经元中表达。该研究的中心假设是来自感觉神经元的 GPA-8 信号将氧传感与身体脂肪含量整合在一起。我们期望了解 GPA-8 在秀丽隐杆线虫中的作用机制将是识别神经回路和 神经系统中的氧感影响身体脂肪含量的保守分子机制。我们的具体目标是： I. 识别调节身体脂肪的表达 GPA-8 的神经元。使用神经元特异性启动子，我们将恢复 gpa-8 突变动物神经元亚群中的 GPA-8 表达，以确定 GPA-8 在调节体脂方面作用的精确解剖位点。二.定义 GPA-8 的细胞内作用模式。 GPA-8 是一种 G¿ 蛋白，表明氧敏感神经元中 G 蛋白信号传导的丧失可以调节身体脂肪。我们将测试 G 蛋白激活周期基因缺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．确定氧感与脂肪储存的整合机制。我们将测试一个涉及 cGMP 信号传导和氧感应的候选遗传通路，以了解不同氧气浓度下体脂的变化，以描绘氧感应和体脂含量整合的神经机制。就预期结果而言，拟议工作的完成将使人们首次深入了解将神经系统中的氧感应与身体脂肪含量联系起来的神经回路和分子机制。重要的是，我们的发现将使我们能够确定控制能量平衡的肠脑轴背后的信号范式。由于所有正在研究的基因都具有明确的哺乳动物直系同源物，因此我们的贡献将对快速识别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，因为神经氧传感和身体脂肪含量之间的分子联系为我们理解有机体能量平衡和肥胖原因提供了一个新的维度。