Regulation of food intake and body weight by dendritically synthesized BDNF

树突状合成的 BDNF 对食物摄入和体重的调节

• 批准号: 7578295
• 负责人: BAOJI XU
• 金额: $ 19.19万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578295
• 关键词: 3' Untranslated Regions; A Mouse; Actins; Address; Appetite Depressants; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cell Nucleus; Data; Dendrites; Dendritic Spines; Desire for food; Drug Delivery Systems; Eating; Excitatory Synapse; Exhibits; Fluorescence; Food Intake Regulation; Galactosidase; Genetic; Genetic Translation; Genotype; Hippocampus (Brain); Human; Hyperphagia; Hypothalamic structure; Impairment; LacZ Genes; Length; Leptin; Long-Term Potentiation; Messenger RNA; Molecular; Monitor; Morbid Obesity; Morphology; Mus; Mutant Strains Mice; Mutation; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Phenotype; Play; Predisposition; Preparation; Protein Biosynthesis; Proteins; Regulation; Reporter; Research Project Grants; Role; Signal Pathway; Sindbis Virus; Site; Structure of nucleus infundibularis hypothalami; Synaptic plasticity; Synaptosomes; System; Testing; Transcript; Translations; Vertebral column; Viral; Virus; base; design; energy balance; improved; link protein; mind control; mutant; neuromechanism; neuron development; neuronal cell body; obesity treatment; postsynaptic; public health relevance

DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) and its TrkB receptor have been implicated in the control of energy balance in both humans and mice. Previous studies suggest that BDNF expressed in the ventromedial hypothalamus (VMH) plays a critical role in regulating energy balance. BDNF protein is synthesized in both neuronal somas and dendrites. In this application, we will examine the role of dendritic local BDNF synthesis in the control of energy balance. Aim 1 is to determine if leptin regulates local synthesis of BDNF in dendrites. We will employ green fluorescence protein reporter constructs and synaptoneurosome preparations to examine the effect of leptin on dendritic transport and translation of BDNF mRNA. Aim 2 is to determine if dendritically synthesized BDNF in the VMH regulates food intake and body weight. We will attempt to rescue the obese phenotype in a Bdnf mouse mutant which lacks dendritic local BDNF synthesis through viral expression of dendritically localized BDNF mRNA or somatically localized BDNF mRNA in the VMH. Aim 3 is to examine if lack of local BDNF synthesis alters morphologies of dendritic spines of TrkB-expressing hypothalamic neurons. There are TrkB-expressing neurons in the hypothalamic nuclei important for the control of energy balance, such as the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH). We will examine spine morphologies of TrkB-expressing neurons in the ARC and DMH in the mouse mutant deficient in local BDNF synthesis. PUBLIC HEALTH RELEVANCE Identification and characterization of new molecules and signaling pathways that control energy balance will offer opportunities for designing improved obesity treatments. If successful, findings from this proposed project will suggest that mutations in proteins involved in transport and translation of dendritic mRNA will increase susceptibility to obesity. Therefore, these proteins could be potential drug targets for obesity treatment.

描述（由申请人提供）：脑衍生的神经营养因子（BDNF）及其TRKB受体与人类和小鼠的能量平衡有关。先前的研究表明，在腹侧下丘脑（VMH）中表达的BDNF在调节能量平衡中起着至关重要的作用。 BDNF蛋白在神经元躯体和树突中均合成。在此应用中，我们将研究树突状局部BDNF合成在能量平衡控制中的作用。目的1是确定瘦素是否调节树突中BDNF的局部合成。我们将采用绿色荧光蛋白报道构建体和突触尿素的制剂，以检查瘦素对树突状转运和BDNF mRNA的翻译的影响。 AIM 2是确定VMH中的树突合成的BDNF是否可以调节食物摄入量和体重。我们将尝试在BDNF小鼠突变体中挽救肥胖的表型，该突变体缺乏树突状局部BDNF合成，通过在VMH中的树突局部局部的BDNF mRNA或体体定位的BDNF mRNA，通过病毒表达来进行。目的3是检查缺乏局部BDNF合成是否改变了表达TRKB下丘脑神经元的树突状刺的形态。下丘脑核中有表达TRKB的神经元对于控制能量平衡很重要，例如弧形核（ARC）和背侧下丘脑（DMH）。我们将检查在局部BDNF合成中缺乏小鼠突变体中表达TRKB神经元的脊柱形态。公共卫生相关性的识别和表征新分子和控制能量平衡的信号通路将为设计改善的肥胖治疗提供机会。如果成功的话，该提议的项目的发现将表明，与树突状mRNA的运输和翻译涉及的蛋白质突变将增加对肥胖症的敏感性。因此，这些蛋白质可能是肥胖治疗的潜在药物靶标。