TrkB Neurons in the Control of Body Weight

TrkB 神经元控制体重

基本信息

批准号：
9108676
负责人：
BAOJI XU
金额：
$ 60.91万
依托单位：
SCRIPPS FLORIDA
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：
2016-04-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108676
关键词：
Acute Adult Body Weight Brain region Brain-Derived Neurotrophic Factor CAV2 gene Canine Adenoviruses Cardiovascular Diseases Cell Nucleus Child Clozapine Consumption Desire for food Drug Targeting Eating Energy Intake Energy Metabolism Equilibrium Food Energy Food Intake Regulation Gene Deletion Gene Expression Gene Expression Profiling Genes Genetic Recombination Goals Human Hyperphagia Hypothalamic structure Infection Injection of therapeutic agent Intervention Label Lead Leptin Life Ligands Link Location LoxP-flanked allele Malignant Neoplasms Maps Measures Mediating Melanocortin 4 Receptor Molecular Monitor Morbid Obesity Motor Activity Mus Neurons Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Non-Insulin-Dependent Diabetes Mellitus Obesity Oxides Pathway interactions Physiological Processes Play Proteins RNA Rabies virus Regulation Research Project Grants Risk Role Signal Pathway Site Synapses System Tamoxifen Technology Thermogenesis Tracer Transcript United States Viral Viral Vector Virus adeno-associated viral vector alpha-Melanocyte stimulating hormone beta-Galactosidase design designer receptors exclusively activated by designer drugs economic cost energy balance leptin receptor neural circuit neuromechanism novel novel therapeutic intervention obesity in children presynaptic presynaptic neurons public health relevance receptor research study

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the mechanism governing the central control of energy balance. Three ligand-receptor pairs have been shown to play a key role in the regulation of energy balance, as deficits in any of these three signaling pathways lead to severe obesity in humans and mice. They are leptin and leptin receptor, alpha-melanocyte-stimulating hormone and melanocortin-4 receptor (MC4R), and brain-derived neurotrophic factor (BDNF) and its receptor TrkB. Great progress has been made in understanding the neural mechanism by which the first two ligand-receptor pairs regulate energy balance. However, very little is known on how the BDNF-TrkB pathway regulates energy balance. Our preliminary studies found that deletion of the TrkB gene in the paraventricular hypothalamus (PVH) caused extreme hyperphagia and severe obesity and that TrkB deletion in the dorsomedial hypothalamus (DMH) led to modest hyperphagia, impaired thermogenesis, reduced locomotor activity, and obesity. These exciting observations lead us to posit that some neural circuits linked to PVHTrkB and DMHTrkB neurons play a key role in regulating appetite and energy expenditure. We propose to demonstrate an important role for PVHTrkB and DMHTrkB neurons in the control of energy balance by deleting the TrkB gene in the PVH and DMH and by activating TrkB neurons in these two nuclei with the DREADD technology, to identify the neural circuits that mediate the effect of TrkB expressed in the PVH and DMH on appetite and energy expenditure using viral tract tracing and projection-specific gene deletion, and to characterize PVHTrkB and DMHTrkB neurons through gene expression profiling.

描述（由适用提供）：该研究项目的长期目标是了解控制能量平衡中心控制的机制。已经证明三个配体受体对在能量平衡的调节中起着关键作用，这在这三种信号传导途径中的任何一个中都会导致人类和小鼠的严重肥胖。它们是瘦素和瘦素受体，α-甲状腺细胞刺激的马酮和黑色素质蛋白-4受体（MC4R）以及脑衍生的神经营养因子（BDNF）及其受体TRKB。在理解前两个配体受体调节能量平衡的神经元机制方面取得了巨大进展。但是，关于BDNF-TRKB途径如何调节能量平衡的知之甚少。我们的初步研究发现，在旁脑室下丘脑（PVH）中的TRKB基因的缺失导致极端的心和严重的肥胖，并且在背侧下丘脑（DMH）中TRKB缺失导致适度的女性体育膜，导致谦虚的女性体现，减轻了热生成，减轻了体积，肥胖。这些令人兴奋的观察结果使我们肯定了一些与PVHTRKB和DMHTRKB神经元相关的神经元电路在确定食欲和能量消耗方面起着关键作用。我们建议通过删除PVH和DMH中的TRKB基因以及通过DREADD技术激活TRKB神经元，通过删除TRKB基因来证明PVHTRKB和DMHTRKB神经元在控制能量平衡中的重要作用，从追踪和投影特异性基因缺失，并通过基因表达分析表征PVHTRKB和DMHTRKB神经元。