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NUCLEUS TRACTUS SOLITARIUS MELANOCORTIN SIGNALING IN THE CONTROL OF FOOD INTAKE

孤束核黑皮质素信号传导控制食物摄入

基本信息

批准号：
8296285
负责人：
Scott Edward Kanoski
金额：
$ 3.09万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-02 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296285
关键词：
1-Phosphatidylinositol 3-Kinase Address Agonist Animal Model Appetite Depressants Basic Science Behavior Biological Assay Body Weight Brain Stem Cell Nucleus Cholecystokinin Chronic Clinical Drug Development Cyclic AMP-Dependent Protein Kinases Data Development Drug Delivery Systems Eating Elements Energy Metabolism Event Feeding behaviors Food Energy Gastrointestinal tract structure Health Hormones Human Hyperphagia Immunoblot Analysis Immunoblotting In Vitro Intake Ligands Link MAPK3 gene Measures Mediating Mediation Mediator of activation protein Melanocortin 4 Receptor Metabolic Metabolic Diseases Methods Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mutation Neurons Nucleus solitarius Nutrient Obesity Overweight Pathway interactions Peptides Peripheral Pharmaceutical Preparations Pharmacological Treatment Physiological Physiology Population Prevalence Production Public Health RNA Interference Receptor Activation Receptor Gene Receptor Signaling Regulation Research Role SHU 9119 Satiation Shapes Signal Pathway Signal Transduction Site Stomach System Techniques Technology computerized data processing gastrointestinal hindbrain in vivo insight melanocortin receptor neurochemistry obesity treatment public health relevance relating to nervous system research study response small hairpin RNA upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Obesity prevalence is dramatically rising in Western cultures creating devastating and costly health problems. Mutations in the melanocortin 4-receptor (MC4-R) gene are the most common monogenetic cause of severe human obesity. The central melanocortin system is a promising target for clinical drug development for the treatment of obesity and related metabolic disorders, as MC4-R agonists potently suppress food intake and body weight in animal models. This proposal is relevant to clinical drug development and public health, as experiments have potential to yield insights into the mechanisms through which MC4-R signaling contributes to food intake suppression. The aims of this proposal are shaped by recent data showing that the nucleus tractus solitarius (NTS) of the caudal brainstem is a critical site of relevance to food intake control by MC4-R ligands, and that caudal brainstem MC4-R signaling is required for food intake suppression by exogenous cholecystokinin (CCK), the intestinally-derived satiation hormone. Experiments proposed in Specific Aim 1 will generate data that are necessary to more fully evaluate the hypothesis that caudal brainstem MC4-R signaling mediates the intake suppression triggered by various GI satiation signals. Caudal brainstem MC4-R antagonist treatment will be used to assess whether or not activation of these receptors is required for intake suppression following endogenous methods of GI satiation signaling, including intraintestinal nutrient delivery and gastric distention. Proposed research will also probe more deeply into the functional site of hindbrain MC4-R mediation of GI signals by examining the effects of parenchymal NTS MC4-R antagonist treatment on intake suppression by CCK. Adeno-associated virally-mediated knockdown of MC4-Rs in the NTS will be used as a complementary approach to antagonist treatment to assess the endogenous role of NTS MC4-Rs in mediating intake suppression by GI satiation signals. Importantly, MC4-R knockdown technology will also be used to assess the role of endogenous NTS MC4-R signaling in energy regulation more generally. Experiments proposed in Specific Aim 2 will expand consideration to the intracellular signaling pathways in the NTS contributing to intake suppression following MC4-R agonists, GI satiation signaling, and their putative combination. Proposed research will build upon our preliminary findings and other recent data by targeting the p44/42 mitogen-activated protein kinase (MAPK) signaling pathway and potential upstream kinases (protein kinase A [PKA] and phosphatidylinositol 3-kinase [PI3K]) as NTS intracellular mediators of intake suppression by MC4-R ligands and GI signals. Experiments will combine in vivo approaches using pharmacological inhibition of p44/42 MAPK, PKA, and PI3K, with in vitro approaches using activity assays and immunoblots, to assess the physiological role of these intracellular signaling pathways in the suppression of intake that follows MC4-R ligands, GI satiation signals, and potentially their combination. Research laid out in this proposal has the potential to deepen the basic science related to neurochemical mediators of food intake suppression. PUBLIC HEALTH RELEVANCE: The prevalence of obese and overweight humans in Western cultures has increased dramatically, leading to devastating and costly health problems. Effective drug treatments for obesity treatment are likely to come from basic science investigating the neuronal controls of food intake behavior. Research proposed here is relevant to clinical drug development for obesity by exploring neurohormonal mediators of food intake suppression following gastrointestinal contact with ingested nutrients and the processing of these signals by the human obesity-linked melanocortin receptors in the caudal brainstem.

描述（由申请人提供）：在西方文化中，肥胖症的流行率急剧上升，造成了毁灭性的和昂贵的健康问题。黑皮质素4受体（MC 4-R）基因突变是人类严重肥胖最常见的单基因原因。中枢黑皮质素系统是用于治疗肥胖症和相关代谢紊乱的临床药物开发的有前景的靶标，因为MC 4-R激动剂在动物模型中有效地抑制食物摄入和体重。这一提议与临床药物开发和公共卫生有关，因为实验有可能深入了解MC 4-R信号传导有助于抑制食物摄入的机制。最近的数据表明，尾侧脑干的孤束核（NTS）是一个关键的网站相关的MC 4-R配体的食物摄入量控制，尾侧脑干MC 4-R信号是所需的食物摄入抑制外源性胆囊收缩素（CCK），垂体来源的饱腹激素。具体目标1中提出的实验将生成更全面地评估尾脑干MC 4-R信号传导介导由各种GI饱足信号触发的摄入抑制的假设所必需的数据。尾侧脑干MC 4-R拮抗剂治疗将用于评估这些受体的激活是否是GI饱足信号传导的内源性方法（包括肠内营养输送和胃扩张）后摄入抑制所需的。拟议的研究还将通过检查实质NTS MC 4-R拮抗剂治疗对CCK抑制摄入的影响，更深入地探讨后脑MC 4-R介导GI信号的功能部位。NTS中MC 4-R的腺相关病毒介导的敲低将用作拮抗剂治疗的补充方法，以评估NTS MC 4-R在通过GI饱足信号介导摄入抑制中的内源性作用。重要的是，MC 4-R敲低技术也将用于更普遍地评估内源性NTS MC 4-R信号传导在能量调节中的作用。具体目标2中提出的实验将扩大对NTS中有助于MC 4-R激动剂、GI饱足信号传导及其假定组合后的摄入抑制的细胞内信号传导途径的考虑。拟议的研究将建立在我们的初步发现和其他最近的数据，通过靶向p44/42丝裂原活化蛋白激酶（MAPK）信号通路和潜在的上游激酶（蛋白激酶A [PKA]和磷脂酰肌醇3-激酶[PI 3 K]）作为NTS细胞内介质的MC 4-R配体和GI信号抑制摄入。实验将结合联合收割机使用p44/42 MAPK、PKA和PI 3 K的药理学抑制的体内方法与使用活性测定和免疫印迹的体外方法，以评估这些细胞内信号传导途径在抑制MC 4-R配体、GI饱足信号和潜在的它们的组合之后的摄入中的生理作用。该提案中提出的研究有可能深化与食物摄入抑制的神经化学介质相关的基础科学。公共卫生关系：在西方文化中，肥胖和超重人群的流行率急剧增加，导致了毁灭性的和代价高昂的健康问题。有效的药物治疗肥胖的治疗可能来自基础科学研究的神经元控制的食物摄入行为。这里提出的研究是相关的肥胖症的临床药物开发，通过探索神经激素介质的食物摄入抑制胃肠道接触摄入的营养物质和这些信号的处理与人类肥胖相关的黑皮质素受体在尾脑干。