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.

项目摘要/摘要 肥胖症的惊人患病率带来了重大的公共卫生和经济后果。有效的抗 由于行为策略有限 成功。内源性饱腹感信号胰高血糖素肽-1（GLP-1）的类似物抑制食物摄入量和 体重，经FDA批准用于肥胖症。但是，GLP-1类似物（例如，半卢宾）是 负担受到副作用的负担，即恶心和呕吐。因此，增加GLP-1的治疗潜力 接收器（GLP-1R）激动剂需要表征介导两种食物的中心机制 GLP-1的进气抑制和恶心/呕吐作用。大鼠中的初步数据表明GLP-1RS 核基因座（LC）是大脑中去甲肾上腺素（NE）的来源，是药物的 与GLP-1的食物摄入量和类似疾病的作用在生理上相关。但是，电路 LC中的内源性GLP-1信号传导有助于食物摄入抑制，恶心/发育作用仍然存在 不清楚。此外，LC GLP-1RS与食物摄入抑制性的功能相关性和 半卢宾的恶心/呕吐作用尚不清楚。 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 过渡到具有独立R01资金的终身助理助理教授。为此，提议 研究将采用多种方法来训练应用程序，以识别行为，蜂窝和电路级别 LC GLP-1R背后的机制诱导厌食和疾病样行为。目的我将使用药物， 大鼠和肌肉sh的化学生成和RNAi介导的GLP-1R敲低策略，一种临床前 具有与人类相似的催眠轮廓的模型，以揭示一个电路，通过该电路，内源性GLP-1信号传导 LC有助于食物摄入抑制，恶心和呕吐。 AIM II将采用翻译方法 确定LC NE神经元的实时钙信号传导动力学以及semaglutide以及 LC GLP-1RS与食物摄入抑制，恶心/雌激素和钙信号的药理相关性 被系统性的semaglutide引起。 AIM II还将使用尖端的单核RNA测序和 生物信息学分析以探测半卢皮德诱导的LC NE神经元转录组的变化，以揭示 LC神经元的指纹和通过半卢替肽对LC NE神经元基因的调节。这些结果 实验将告知开发更有效，更耐受的肥胖症，并将提供 具有独特技能和试点数据的申请人，以鼓励她过渡到研究独立性。