Integrative Physiology of Obesity: Role of GPR160

肥胖的综合生理学：GPR160 的作用

• 批准号: 10208871
• 负责人: Gina L.C. Yosten
• 金额: $ 37.88万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208871
• 关键词: Agonist; Animal Model; Animals; Appetite Regulation; Automobile Driving; Binding; Biological; Biological Assay; Biotin; Brain Stem; Brain region; CARTPT gene; CRISPR/Cas technology; Cell Nucleus; Co-Immunoprecipitations; Data; Desire for food; Development; Eating; Eating Disorders; Endocrine; Exposure to; Feedback; Fiber; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic Models; Health; Healthcare Systems; High Fat Diet; Hormone secretion; Hypothalamic structure; Injections; Intake; Investigation; Knockout Mice; Ligands; Ligase; Ligation; LoxP-flanked allele; MAP Kinase Gene; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Microscopy; Modeling; Molecular; Molecular Conformation; Mus; Neurons; Neurotransmitters; Obesity; Orphan; Pain; Pathway interactions; Pattern; Peptides; Peripheral; Pertussis; Phosphorylation; Physiology; Play; Predisposition; Process; Proteins; Rattus; Regulation; Research; Resolution; Role; Signal Transduction; Site; Stress; Sucrose; Techniques; Testing; Therapeutic; Work; analog; beta-arrestin; blood glucose regulation; body system; cocaine receptor; diet-induced obesity; feeding; glucagon-like peptide 1; individual patient; innovation; knock-down; mRNA Expression; male; novel therapeutic intervention; novel therapeutics; obesity treatment; receptor; small hairpin RNA; tool

PROJECT SUMMARY/ABSTRACT Peptide neurotransmitters play important roles in the neuronal networks regulating appetite in several brain regions, including brainstem feeding centers such as the nucleus tractus solitarius (NTS) and hypothalamus. One such peptide, cocaine- and amphetamine-regulated transcript (CART), appears to act as a downstream mediator integrating peripheral metabolic signals including glucagon like peptide 1 and cholesytokinin. Central injection of CART inhibits food intake in multiple animal models and global deletion of CART leads to exaggerated food intake and increased susceptibility to a high fat diet in mice. Additionally, central CART neurons appear to play a role in whole body glucose homeostasis and meal patterning. To date, the identity of the CART receptor(s) has remained elusive, thus limiting the therapeutic potential of CART analogs for the treatment of obesity and associated eating disorders. CART activates downstream signaling cascades typical of those associated with G protein coupled receptors (GPCRs). Using our unique Deductive Reasoning Ligand-Receptor matching strategy, we identified the orphan GPCR, GPR160, to be a receptor for CART. In this Research Plan, we propose to test the overall hypotheses that activation of GPR160 is necessary for the biologic effect of CART peptides and that endogenous GPR160 plays a significant role in the regulation of appetite and metabolic function. We will test these hypotheses in four Specific Aims using a combination of cutting edge molecular techniques and innovative animal models. S.A. 1: Examine the functional and physical relationship between CART and GPR160. S.A. 2: Investigate the role of endogenous GPR160 in the short-term regulation of appetite and metabolism. S.A. 3: Investigate the role of endogenous GPR160 in the hypothalamic regulation of appetite and stress hormone secretion. S.A. 4: Establish a genetic model of GPR160 absence to investigate the importance of the receptor in the long term regulation of metabolic function. The proposed studies will further evaluate the functional and physical relationship between GPR160 and CART, establish CART and GPR160 as an important ligand-receptor pair in the short term and long term regulation of metabolic function, and produce innovative research tools, such as the GPR160-flox rat.

项目摘要/摘要 多肽类神经递质在几个脑内调节食欲的神经网络中发挥重要作用 区域，包括脑干喂养中心，如孤束核(NTS)和下丘脑。 其中一种多肽，可卡因和安非他明调节的转录本(CART)，似乎扮演着下游的角色 整合外周代谢信号的介体，包括胰升糖素样肽1和胆碱能激肽。中环 在多种动物模型中注射CART抑制食物摄取，CART的全局缺失导致 夸大食物摄入量，增加小鼠对高脂肪饮食的易感性。此外，中央购物车 神经元似乎在全身葡萄糖动态平衡和进食模式中发挥作用。到目前为止， CART受体(S)仍然难以捉摸，因此限制了CART类似物治疗卵巢癌的潜力 肥胖症及相关饮食失调的治疗。CART激活下游信令级联 与G蛋白偶联受体(GPCRs)相关的基因。使用我们独特的演绎推理 通过配基-受体匹配策略，我们确定了孤儿GPR160是CART的受体。在……里面 在这项研究计划中，我们建议测试GPR160激活对于 CART多肽的生物学效应及内源性GPR160在细胞周期调控中的作用 食欲和代谢功能。我们将在四个特定目标中使用以下组合来测试这些假设 尖端分子技术和创新的动物模型。 S.A.1：检查CART和GPR160之间的功能和物理关系。 S.A.2：研究内源性GPR160在短期调节中的作用 食欲和新陈代谢。 研究内源性GPR160在下丘脑调节食欲和压力中的作用 荷尔蒙分泌。 S.A.4：建立GPR160缺失的遗传模型以研究GPR160缺失的重要性 受体在代谢功能的长期调节中的作用。 拟议的研究将进一步评估GPR160和GPR160之间的功能和物理关系 CART，使CART和GPR160在短期和长期内成为重要的配体-受体对 调节代谢功能，并生产创新的研究工具，如GPR160-FLOX大鼠。