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Ciliary Mchr 1 Signaling in Feeding Behavior and Obesity

睫状 Mchr 1 信号在进食行为和肥胖中的作用

基本信息

批准号：
9894792
负责人：
Nicolas F Berbari
金额：
$ 35.07万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-20 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894792
关键词：
Address Adenylate Cyclase Adult Affect Agonist Alstrom syndrome American Animal Model Appetite Depressants Area Arrestins Bardet-Biedl Syndrome Biochemical Body Composition Body Weight Body Weight decreased Brain Brain region Calcium Cell membrane Cells Cilia Clinical Complex Coupled Cyclic AMP Cytoplasm Data Desire for food Development Diabetes Mellitus Diet Disease Eating Electrophysiology (science)Etiology Feeding behaviors Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Genetic Diseases Goals Health Healthcare Systems Heart Diseases Homeostasis Hyperphagia Hypothalamic structure In Vitro Knock-out Leptin Ligands MCHR1 gene Mediating Membrane Microtubules Modeling Modernization Molecular Morbidity - disease rate Motor Activity Mus Mutant Strains Mice Mutation Neurons Obesity Organelles Overweight Pathway interactions Patients Pharmacology Phenotype Physiological Population Premature Mortality Proteins Publishing Receptor Signaling Regulation Rewards Rhodopsin Role Satiation Science Second Messenger Systems Sensory Signal Pathway Signal Transduction Smell Perception Societies Stroke Testing Therapeutic United States Vision Work appendage base blood glucose regulation ciliopathy comorbidity cost desensitization design energy balance experimental study feeding human model imaging approach in vivo in vivo evaluation interest live cell imaging metabolic rate mortality mouse model multi-electrode arrays mutant novel therapeutic intervention olfactory receptor rare condition receptor response social

项目摘要

PROJECT SUMMARY Obesity is a major cause of premature mortality due to its associated co-morbidities such as diabetes, heart disease and stroke. Two-thirds of adults in the United States are overweight, adding immense costs to the healthcare system. Although once considered to be a social issue of overindulgence, modern science has revealed a profound effect of genetics on body weight. Rare monogenetic forms of obesity in humans and animal models have revealed that the regulation of energy balance is complex, involving numerous intertwined signaling pathways. Both Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are genetic disorders that present with increases in eating and obesity. These rare syndromes are examples of ciliopathies, a class of genetic disorders that have cilia dysfunction as their etiological basis. Primary cilia are small, solitary, microtubule based cellular appendages that were long thought to be vestigial organelles. Thus, it was surprising that their dysfunction was associated with obesity in both humans and animal models. Disruption of cilia specifically within the brain of mice results in hyperphagia associated obesity. Recent work has implicated cilia or their associated proteins in coordinating leptin signaling, although this remains controversial and unclear. It has also recently been shown that several G-protein coupled receptors preferentially localize to the cilia of neurons. How these ciliary receptors and signaling pathways may impact feeding behavior and obesity also remains unclear. The goal of this project is to determine if altered signaling through a specific ciliary receptor that is known to have a role in feeding behavior, melanin concentrating hormone receptor 1, contributes to the obesity phenotype. A strong understanding of the connection between cilia and obesity could open new therapeutic approaches to address one of the most clinically important issues impacting the health of the American populace.

项目概要肥胖是导致过早死亡的主要原因，因为肥胖与糖尿病等相关并发症有关。心脏病和中风。美国三分之二的成年人体重超重，这给人们的生活增加了巨大的成本医疗保健系统。尽管一度被认为是过度放纵的社会问题，但现代科学已经揭示了遗传对体重的深远影响。人类和动物罕见的单基因肥胖形式模型显示能量平衡的调节是复杂的，涉及许多相互交织的信号途径。 Bardet-Biedl 综合征 (BBS) 和 Alström 综合征 (ALMS) 都是遗传性疾病，随着饮食和肥胖的增加。这些罕见的综合征是纤毛病的例子，纤毛病是一类遗传性疾病以纤毛功能障碍为病因的疾病。初级纤毛小、单生、基于微管长期以来被认为是退化细胞器的细胞附属物。因此，令人惊讶的是，他们的在人类和动物模型中，功能障碍与肥胖有关。纤毛的破坏特别是在小鼠大脑会导致饮食过多相关的肥胖。最近的工作涉及纤毛或其相关的协调瘦素信号传导的蛋白质，尽管这仍然存在争议和不清楚。最近也有研究表明，几种 G 蛋白偶联受体优先定位于神经元的纤毛。这些如何纤毛受体和信号通路可能会影响进食行为，而肥胖也仍不清楚。这该项目的目标是确定通过已知具有特定纤毛受体的信号传导是否发生改变黑色素浓缩激素受体 1 在进食行为中的作用有助于肥胖表型。一个对纤毛和肥胖之间关系的深入了解可以为治疗肥胖症开辟新的治疗方法解决影响美国民众健康的最重要的临床问题之一。