Examining the role of locus coeruleus glucagon-like peptide-1 receptors in feeding behavior

检查蓝斑胰高血糖素样肽-1 受体在摄食行为中的作用

• 批准号: 10664322
• 负责人: Samantha Fortin
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664322
• 关键词: Affect; Agonist; Anatomy; Anorexia; Anti-Obesity Agents; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; Bioinformatics; Body Weight; Body Weight decreased; Brain; Calcium Signaling; Cell Nucleus; Complex; Computer software; Data; Dedications; Development; Development Plans; Eating; Economics; Electrophysiology (science); Emetics; FDA approved; Feeding behaviors; Fingerprint; Funding; Future; GLP-I receptor; Genes; Genetic; Glutamates; Goals; Human; In Situ Hybridization; Individual; Ingestion; Investigation; Kaolin; Ligands; Mediating; Microinjections; Mus; Nature; Nausea; Nausea and Vomiting; Neuroanatomy; Neurons; Norepinephrine; Obesity; Obesity Epidemic; Output; Pathway interactions; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Pica Disease; Population; Pre-Clinical Model; Presynaptic Terminals; Prevalence; Proxy; Public Health; RNA Interference; Rattus; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research; Role; Satiation; Scientist; Shrews; Sick Role; Signal Pathway; Signal Transduction; Site; Source; Testing; Therapeutic; Therapeutic Effect; Time; Training; Virus; Vomiting; analog; antagonist; behavioral pharmacology; career development; clay; combat; exenatide; experimental study; feeding; glucagon-like peptide 1; glutamatergic signaling; hindbrain; human model; improved; in vivo calcium imaging; insight; integrated circuit; knock-down; locus ceruleus structure; mind control; neural; noradrenergic; novel; obesity treatment; parabrachial nucleus; pharmacologic; preproglucagons; presynaptic; professor; reduced food intake; response; side effect; single nucleus RNA-sequencing; skills; success; tenure track; transcriptome; transcriptomics; translational approach

Project Summary/Abstract The staggering prevalence of obesity presents major public health and economic consequences. Effective anti- obesity drugs are desperately needed to combat the obesity epidemic, as behavioral strategies offer limited success. Analogs of the endogenous satiety signal glucagon-like peptide-1 (GLP-1) suppress food intake and body weight and are FDA-approved for obesity treatment. However, GLP-1 analogs (e.g. semaglutide) are burdened by side effects, namely nausea and emesis. Therefore, increasing the therapeutic potential of GLP-1 receptor (GLP-1R) agonists requires characterization of the central mechanisms that mediate both the food intake-suppressive and nausea/emesis effects of GLP-1. Preliminary data in the rat indicate that GLP-1Rs in the locus coeruleus (LC), a source of norepinephrine (NE) output in the brain, are pharmacologically and physiologically relevant for the food intake and illness-like effects of GLP-1. However, the circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression and nausea/emesis remains unclear. Additionally, the functional relevance of LC GLP-1Rs to the food intake suppressive and nausea/emesis effects of the semaglutide is not known. The main goal of the proposed 5- year research career development plan is to facilitate the applicant’s transition to a tenure-track Assistant Professor with independent R01 funding. To this end, the proposed research will train the applicant in a variety of approaches to identify the behavioral, cellular, and circuit-level mechanisms behind LC GLP-1R induced anorexia and illness-like behaviors. Aim I will utilize pharmacological, chemogenetic and RNAi-mediated GLP-1R knockdown strategies in the rat and musk shrew, a preclinical model that has an emetic profile similar to humans, to reveal a circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression, nausea and emesis. Aim II will take a translational approach by determining the real-time calcium signaling dynamics of LC NE neurons to semaglutide as well as the pharmacological relevance of LC GLP-1Rs to the food intake suppression, nausea/emesis and calcium signaling evoked by systemic semaglutide. Aim II will use also cutting-edge single nucleus RNA sequencing and bioinformatic analysis to probe semaglutide-induced changes in the LC NE neuron transcriptome to reveal the fingerprint of LC neurons and regulation of LC NE neuron genes by semaglutide. Results from these experiments will inform the development of more efficacious and tolerated obesity treatments and will provide the applicant with a unique set of skills and pilot data to encourage her transition to research independence.

项目概要/摘要 肥胖症的惊人流行带来了重大的公共卫生和经济后果。有效抗 迫切需要肥胖药物来对抗肥胖流行，因为行为策略提供的药物有限 成功。内源性饱腹感信号胰高血糖素样肽-1 (GLP-1) 的类似物可抑制食物摄入， 体重，并经 FDA 批准用于肥胖治疗。然而，GLP-1 类似物（例如索马鲁肽） 受到副作用的困扰，即恶心和呕吐。因此，增加 GLP-1 的治疗潜力 受体 (GLP-1R) 激动剂需要表征介导食物和 GLP-1 的摄入抑制和恶心/呕吐作用。大鼠的初步数据表明，GLP-1Rs 蓝斑 (LC) 是大脑中去甲肾上腺素 (NE) 输出的来源，具有药理学和 与 GLP-1 的食物摄入和疾病样作用具有生理相关性。然而，该电路 LC 中的内源性 GLP-1 信号传导有助于抑制食物摄入并导致恶心/呕吐持续存在 不清楚。此外，LC GLP-1R 与食物摄入抑制和 索马鲁肽的恶心/呕吐作用尚不清楚。 拟议的五年研究职业发展计划的主要目标是促进申请人的 过渡到终身教授助理教授并获得独立的 R01 资助。为此，建议 研究将培训申请人采用多种方法来识别行为、细胞和电路水平 LC GLP-1R 诱导厌食和疾病样行为背后的机制。目标我将利用药理学， 大鼠和麝鼩的化学遗传学和 RNAi 介导的 GLP-1R 敲低策略（一种临床前研究） 该模型具有与人类相似的催吐特征，以揭示内源性 GLP-1 信号通路 LC 会导致食物摄入抑制、恶心和呕吐。目标 II 将采取转化方法 确定 LC NE 神经元对索马鲁肽的实时钙信号动力学以及 LC GLP-1R 与食物摄入抑制、恶心/呕吐和钙信号传导的药理学相关性 由全身性索马鲁肽引起。 Aim II 还将使用尖端的单核 RNA 测序和 生物信息分析探测索马鲁肽诱导的 LC NE 神经元转录组变化，揭示 LC神经元的指纹和司马鲁肽对LC NE神经元基因的调节。这些结果 实验将为开发更有效和更耐受的肥胖治疗提供信息，并将提供 申请人拥有一套独特的技能和试点数据，以鼓励她过渡到独立研究。