Defensins as Melanocortin Ligands

作为黑皮质素配体的防御素

基本信息

批准号：
8585059
负责人：
Carrie Haskell-Luevano
金额：
$ 41.65万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8585059
关键词：
ART protein Adverse effects Affect Age Agonist Binding Biological Body mass index Brain Chemistry Communities Corticotropin Country Coupled Cyclic AMP Data Defensins Developed Countries Diet Disease Eating Exercise Family Family member Fatty acid glycerol esters Figs - dietary G Protein-Coupled Receptor Genes GTP-Binding Proteins Genes Genetic Genetic Transcription Gland Goals Heart Diseases Homeostasis Human Hyperphagia Hypertension In Vitro Knowledge Ligands Link Malignant Neoplasms Marketing Mediating Melanocortin 3 Receptor Melanocortin 4 Receptor Modification Molecular Molecular Probes Morbidity - disease rate Mus Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Nucleotides Obesity Outcome Pathway interactions Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Physiological Pigmentation physiologic function Pro-Opiomelanocortin Regulation Reporting Research Research Project Grants Risk Factors Role Signal Transduction Stroke Therapeutic Therapeutic Agents Transcript United States Validation Weight Work base beta-Defensins design insight interdisciplinary approach melanocortin receptor member molecular recognition novel public health relevance receptor receptor function response tool

项目摘要

DESCRIPTION (provided by applicant): Obesity afflicts millions of people, and is a major risk factor for Type II diabetes and morbidity. The melanocortin pathway has been clearly identified in mice and humans to be involved in the regulation of obesity and energy homeostasis. Five melanocortin genetic factors that have been identified as being involved in energy homeostasis (the proopiomelanocortin agonists, Agouti and Agouti-related protein antagonists, and the melanocortin-4 receptor and the melanocortin-3 receptor proteins). In 2007, endogenous beta-defensin peptides were reported to participate in the melanocortin pathway. To date, a very limited number of "safe and effective" drugs that result in decreased obesity are currently marketed or in the pipeline. There are many reasons for this, however a critical obstacle is that not all the molecules, factors, proteins, receptors, and pathways that are involved in obesity have been identified and mechanistically characterized. One such example is the beta-defensins. Our working hypothesis is that the endogenous beta-defensin ligands regulate melanocortin receptor function. It is unclear the specific molecular interactions and mechanisms by which the beta-defensins interact with the melanocortin receptors. Are they agonists or antagonists? What are the receptor subtype selectivity profiles? What are the putative ligand-receptor interactions? The proposed multidisciplinary approaches to answer the above questions include chemistry and in vitro receptor pharmacology. This proposal seeks to clarify this novel endogenous melanocortin receptor ligand family, gain fundamental knowledge, and develop molecular probes to use to determine their potential involvement with obesity and Type 2 diabetes.

描述（由申请人提供）：肥胖症遭受了数百万的人，是II型糖尿病和发病率的主要危险因素。在小鼠和人类中清楚地鉴定出黑色皮质素途径参与肥胖和能量稳态的调节。五个已被确定为参与能量稳态的黑色素皮质遗传因子（proopiomelanocortin agonists，Agouti和Agouti相关蛋白拮抗剂，黑色素质蛋白-4受体以及黑色素皮质素-3受体蛋白）。 2007年，据报道内源性β-防御素肽参与黑色素皮质素途径。迄今为止，目前正在销售或在管道中销售少量的“安全有效”药物，导致肥胖症降低。造成这种情况的原因有很多，但是一个关键的障碍是，并非所有涉及肥胖症的分子，蛋白质，受体和途径的所有分子，蛋白质，受体和途径已经鉴定出来并具有机理的特征。一个这样的例子就是β-防御素。我们的工作假设是内源性β-防御素配体调节黑素皮质素受体功能。目前尚不清楚β-防御素与黑色素皮质素受体相互作用的特定分子相互作用和机制。他们是激动剂还是对手？受体亚型选择性曲线是什么？假定的配体 - 受体相互作用是什么？提出的回答上述问题的多学科方法包括化学和体外受体药理学。该提案旨在阐明这种新型内源性黑色皮质素受体配体家族，获得基本知识，并开发用于确定其潜在参与肥胖和2型糖尿病的分子探针。