权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Charting vagal circuits containing glucagon-like peptide 1 receptor

绘制含有胰高血糖素样肽 1 受体的迷走神经回路

基本信息

批准号：
9222742
负责人：
STEPHEN Daniel LIBERLES
金额：
$ 38.14万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222742
关键词：
Ablation Afferent Neurons Agonist Anatomy Axon Behavioral Biology Blood Pressure Body Weight Brain Brain Stem Breathing Cells Cellular biology Clinical Collection Complex Cre-LoxP Cues Data Dependovirus Desire for food Diabetes Mellitus Digestion Diphtheria Toxin Disease Economic Inflation Electric Stimulation Feeding behaviors Foundations Future GCG gene GLP-I receptor Ganglia Genetic Genetic Identity Genetic Techniques Health Heart Heart Rate Homeostasis Hormones Hypothalamic structure Imaging Techniques In Vitro Infection Insulin Intake Intestines Irritants Knock-in Mouse Location Lung Maps Measures Mediating Metabolic Metabolic Diseases Metabolism Methods Molecular Genetics Mus Nausea Neurons Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Operative Surgical Procedures Organ Pattern Peripheral Physiological Physiology Procedures Property Resolution Respiration Role Route Satiation Sensory Specificity Stimulus Stomach Stretching Techniques Technology Therapeutic Tissues Tracer Trachea Vagotomy Vagus nerve structure Virus Diseases afferent nerve aortic arch base blood glucose regulation calcium indicator cell type cohort diabetes control drug development feeding genetic approach glucagon-like peptide 1 improved in vivo in vivo imaging insight mimicry neural circuit neuroregulation novel optogenetics public health relevance receptor relating to nervous system response sensory mechanism sensory stimulus therapy design therapy development tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Glucagon-like peptide 1 (GLP1) is a hormone that controls energy homeostasis, insulin release, and feeding behavior. GLP1 activates a complex neuroendocrine axis that coordinates systemic behavioral and metabolic responses to nutrient intake, with GLP1 receptor (GLP1R) expressed in many locations, including the vagus nerve, brainstem, and hypothalamus. The roles of some GLP1-responsive neurons remain poorly defined, in part due to a lack of appropriate genetic tools. Understanding the roles of different GLP1-responsive neurons is imperative, as therapeutic strategies that involve mimicry or stabilization of GLP1 provide clinically important methods for control of diabetes and potentially other metabolic disorders. GLP1R is expressed in a cohort of vagal sensory neurons, although the roles of vagal GLP1R neurons in feeding behavior, metabolism, and nausea are highly controversial. Recent studies indicate that vagal GLP1R is not required for the effects of GLP1R agonists on body weight or diabetes resolution, raising basic questions about (1) where vagal GLP1R neurons project in the body and brain, (2) what they detect, and (3) what physiological responses they evoke, all of which are unknown. In preliminary data, we used a molecular and genetic approach to deconstruct the sensory vagus nerve into cellular components. We generated a collection of 'ires-Cre' knock-in mice, including Glp1r-ires-Cre mice, and adapted powerful genetic techniques for connectivity mapping, in vivo imaging, and optogenetic control of neural activity in the vagus nerve. Using these approaches, we identified two subtypes of vagal afferents that innervate the lung, and exert powerful and opposing effects on breathing (Cell, 2015), and here, will use related techniques to study the sensory biology of vagal GLP1R neurons. In Aim 1, we developed a strategy for introducing genetic tracers into vagal sensory neurons by adeno-associated virus infection, and will use this technique to map the projections of vagal GLP1R neurons in peripheral organs and the brainstem. In Aim 2, we developed a novel in vivo imaging paradigm in vagal ganglia that involves a genetically encoded calcium indicator, and will use this technique to query the specific response properties of vagal GLP1R neurons. In Aim 3, we will selectively activate or eliminate vagal GLP1R neurons using genetic approaches, and determine the impact on feeding behavior, metabolism, nausea, and other aspects of autonomic physiology. Together, these studies will provide needed information about the cell biology of vagal GLP1R neurons. Charting GLP1- responsive circuits at a cellular level will help reveal how GLP1 evokes diverse physiological responses in health and disease, and may provide an important foundation for future therapy development.

描述(申请人提供)：胰升糖素样肽1(GLP1)是一种控制能量平衡、胰岛素释放和摄食行为的激素。GLP1激活一个复杂的神经内分泌轴，协调系统对营养摄入的行为和代谢反应，GLP1受体(GLP1R)在许多位置表达，包括迷走神经、脑干和下丘脑。一些GLP1反应神经元的作用仍然不明确，部分原因是缺乏适当的遗传工具。了解不同的GLP1反应神经元的作用是当务之急，因为涉及GLP1模拟或稳定的治疗策略为控制糖尿病和潜在的其他代谢疾病提供了临床上重要的方法。GLP1R在一组迷走神经感觉神经元中表达，尽管迷走神经GLP1R神经元在摄食行为、代谢和恶心中所起的作用仍存在很大争议。最近的研究表明，迷走神经GLP1R不是GLP1R激动剂对体重或糖尿病缓解所必需的，这引发了以下基本问题：(1)迷走神经GLP1R神经元在身体和大脑中投射到哪里，(2)它们检测到什么，以及(3)它们引起什么生理反应，所有这些都是未知的。在初步数据中，我们使用分子和遗传学方法将感觉迷走神经分解成细胞成分。我们产生了一组‘Ires-Cre’敲入小鼠，包括GLP1R-Ires-Cre小鼠，并采用了强大的基因技术来绘制连接性图谱、活体成像和迷走神经神经活动的光遗传控制。使用这些方法，我们确定了两种亚型的迷走神经传入，它们支配肺，并对呼吸产生强大和相反的影响(Cell，2015)，在这里，我们将使用相关技术来研究迷走神经GLP1R神经元的感觉生物学。在目标1中，我们开发了一种通过腺相关病毒感染将遗传示踪剂引入迷走感觉神经元的策略，并将使用这一技术来定位迷走神经GLP1R神经元在外周器官和脑干中的投射。在目标2中，我们开发了一种新的迷走神经节体内成像范式，其中包括一个遗传编码的钙指示剂，并将使用这一技术来询问迷走神经节GLP1R神经元的特异性反应特性。在目标3中，我们将使用遗传方法选择性地激活或消除迷走神经GLP1R神经元，并确定对摄食行为、新陈代谢、恶心和其他自主生理方面的影响。总之，这些研究将为迷走神经GLP1R神经元的细胞生物学提供必要的信息。在细胞水平上绘制GLP1反应回路将有助于揭示GLP1如何在健康和疾病中引起不同的生理反应，并可能为未来的治疗开发提供重要的基础。