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.

项目总结/摘要 肥胖症的惊人流行带来了重大的公共健康和经济后果。有效抗- 迫切需要肥胖药物来对抗肥胖流行病，因为行为策略提供有限的 成功内源性饱腹感信号胰高血糖素样肽-1（GLP-1）的类似物抑制食物摄入， 是FDA批准的肥胖治疗药物。然而，GLP-1类似物（例如Semaglutide） 有副作用，即恶心和呕吐。因此，增加GLP-1的治疗潜力 受体（GLP-1 R）激动剂需要表征介导食物 GLP-1的摄取抑制和恶心/呕吐作用。大鼠中的初步数据表明， 蓝斑（LC）是脑中去甲肾上腺素（NE）输出的来源， 与GLP-1的食物摄入和疾病样作用生理学相关。然而，电路， LC中的内源性GLP-1信号传导有助于食物摄入抑制和恶心/呕吐仍然存在 不清楚此外，LC GLP-1 R与食物摄入抑制和 Semaglutide的恶心/呕吐效应尚不清楚。 拟议的5年研究职业发展计划的主要目标是促进申请人的 过渡到终身制助理教授与独立的R 01资金。为此，建议 研究将培训申请人在各种方法，以确定行为，细胞和电路水平 LC GLP-1 R诱导厌食和疾病样行为的机制。目的利用药理学， 在大鼠和麝鼩中的化学遗传学和RNAi介导的GLP-1 R敲低策略， 具有与人类相似的呕吐特征的模型，以揭示内源性GLP-1信号传导在 LC导致食物摄入抑制、恶心和呕吐。Aim II将采取一种转化方法， 确定LC NE神经元对Semaglutide的实时钙信号传导动力学以及 LC GLP-1 R与摄食抑制、恶心/呕吐和钙信号传导的药理学相关性 全身性Semaglutide诱发。Aim II还将使用最先进的单核RNA测序技术， 生物信息学分析，以探测Semaglutide诱导的LC NE神经元转录组的变化，以揭示 LC神经元的指纹图谱和Semaglutide对LC NE神经元基因的调节。从这些 实验将为开发更有效和更耐受的肥胖治疗提供信息， 申请人拥有一套独特的技能和试点数据，以鼓励她向独立研究过渡。