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

基本信息

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
项目类别：
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

项目摘要

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。迫切需要通过药物来对抗肥胖流行病，因为行为策略提供的药物有限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并取得成功。然而，GLP-1 类似物（例如索马鲁肽）已获得 FDA 批准用于肥胖治疗。因此，增加了 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 在大鼠中的摄入抑制和恶心/呕吐作用。蓝斑 (LC) 是大脑中去甲肾上腺素 (NE) 输出的来源，具有药理学和然而，GLP-1 的食物摄入和疾病样作用与生理相关。 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/呕吐持续存在此外，LC GLP-1R 与食物摄入抑制和功能相关性尚不清楚。索马鲁肽的恶心/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拥有独立 R01 资助的终身教授助理教授。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 I 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 有助于抑制食物摄入、恶心和呕吐，Aim 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 Aim II 还将使用尖端的单核 RNA 测序和系统性索马鲁肽引发。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 神经元的指纹以及索马鲁肽对 LC NE 神经元基因的调节。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。