Identification of enhancers of energy expenditure via SLN/SERCA interaction

通过 SLN/SERCA 相互作用鉴定能量消耗增强剂

基本信息

批准号：
8967738
负责人：
Naresh Chandra Bal
金额：
$ 12.26万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2016-06-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8967738
关键词：
ATP Hydrolysis Accounting Address Adult Affect Am 80 Amino Acids Animals Anti-Obesity Agents Binding Bioenergetics Biogenesis Biological Assay Biological Factors Brown Fat Ca(2+)-Transporting ATPase Capsaicin Cell Respiration Cells Chemicals Consumption Data Diet Energy Metabolism Enhancers Ephedrine Fatty acid glycerol esters Futile Cycling Goals Grant Health Health Care Costs Healthcare Human Human Genetics Integral Membrane Protein Investigation Lead Ligand Binding Ligands Mediating Medicine Metabolic Metabolic Diseases Minor Mitochondria Modeling Molecular Mus Muscle Mutation Nature Obesity Pharmaceutical Chemistry Pharmacologic Substance Pharmacy facility Phenotype Play Population Property Proteins Publications Publishing Pump Recruitment Activity Reporting Research Resistance Reticulum Role Side Site Skeletal Muscle Staging Structural Chemistry Structural Models Structure Structure-Activity Relationship Testing Thermogenesis Time Tissues Up-Regulation Work analog animal tissue base cellular targeting college design improved inhibitor/antagonist insight novel novel strategies obesity treatment overexpression pharmacophore public health relevance sarcolipin screening small molecule small molecule libraries treatment strategy uncoupling protein 1 ursolic acid

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major health problem in the USA and the accumulated health cost due to obesity alone was reported to be ~80 billion USD in the year 2010, which is projected to cross 350 billion USD by the year 2025. Research in the last two decades has shown that in majority of the cases obesity is due to energy surplus and can be treated by increasing energy expenditure. In spite of significant progress in the understanding about ways to target cellular bioenergetics to increase energy expenditure most of these are reliant on uncoupling protein 1 (UCP1)-based mechanisms, that is a minor component in most adult human beings. Therefore, alternative mechanism of thermogenesis should be paid equal importance to enhance energy expenditure to treat obesity. We have recently discovered a novel thermogenic mechanism by a protein called Sarcolipin (SLN), published in Nature Medicine in 2012. SLN is a 31 amino acid single transmembrane protein, that regulate the function of SERCA pump. Binding of SLN to SERCA promotes uncouple ATP hydrolysis of SERCA pump from Ca2+ transport leading to futile cycling and increased ATP utilization contributing to muscle-based non-shivering thermogenesis (NST). We have shown that loss of SLN predisposes mice to develop obesity on high fat diet (HFD) but upregulation of SLN provide protection against HFD-induced obesity. Our next study shows that skeletal muscle specific overexpression of SLN drives mitochondrial biogenesis and fuels oxidative metabolism in skeletal muscle providing resistance to obesity, is under final stages of publication. Further, genetic alteration in chromosomal locus containing SLN has also been shown to be associated with obesity in humans, suggesting SLN-mediated energy consumption may be a factor in obesity. Skeletal muscle constitutes ~40% of mammalian body mass and accounts for ~80% of metabolic substrate consumption. Therefore skeletal muscle offers an ideal target to increase energy expenditure, pharmacologically as a strategy for the treatment of obesity. In this application, I propose to identify lead compounds enhancing SLN-mediated skeletal muscle-based energy expenditure, using a multifaceted approach including studies at the whole animal, tissue, cell and computational levels. I have data to indicate that capsaicin enhances SLN-SERCA binding. I have also developed a cell-based assay to screen compounds with ability to enhance SLN-mediated uncoupling of SERCA. I have designed and synthesized four different capsaicin analogs, by modifying the side-chains. My preliminary data suggest that one these four capsaicin-analogs possess better activity than capsaicin itself. These facts provide more confidence in my initial hypothesis and I propose the following three aims towards achieving my final goal. In Aim 1, I will try to identify the best capsaicin-analog to increase SLN-mediated energy expenditure and anti- obesity lead. In Aim 2, I will further explore other classes of compounds (many chemical libraries are available in college of pharmacy on campus) known to affect SERCA function and/or increase energy consumption, to Identify chemicals that increase SLN-mediated uncoupling of SERCA and possess anti-obesity activity. In AIM 3, I am working to develop a responsive atomistic model of SLN-SERCA-ligand interaction to define the pharmacophores and optimize the shortlisted anti-obesity agents. We believe that identification of chemical compounds with ability to enhance SLN action on SERCA will provide an exciting new opportunity to pharmacologically increase muscle-based energy consumption and control obesity.

描述（适用提供）：肥胖是美国的一个主要健康问题，据报道，仅肥胖造成的累积健康成本在2010年约为800亿美元，预计到2025年将超过3500亿美元。在过去的两十年中，在过去的二十年中，大多数情况下，大多数情况下，肥胖的大部分可以通过能量过剩而受到能量造成的培训，并且可以增加肥胖的培训。尽管在理解靶向细胞生物能力以增加能量消耗的方法方面取得了重大进展，其中大多数依赖于基于蛋白1（UCP1）的机制，这在大多数成人人类中都是次要组成部分。因此，应为增强肥胖症的能量消耗而付出同等重要的替代机制。我们最近通过一种名为Sarcolipin（SLN）的蛋白质发现了一种新型的热机制，该蛋白于2012年发表在自然医学上。SLN是一种31个氨基酸单跨膜蛋白，可调节SERCA泵的功能。 SLN与SERCA的结合促进了SERCA泵的Uncouple ATP水解，从Ca2+转运导致徒劳的循环和增加的ATP利用率增加，导致基于肌肉的非动摇热生成（NST）。我们已经表明，SLN的损失使小鼠在高脂饮食（HFD）上产生肥胖症（HFD），但SLN的上调提供了针对HFD诱导的肥胖症的保护。我们的下一项研究表明，SLN的骨骼肌特异性过表达驱动线粒体生物发生，并在骨骼肌中为氧化物代谢提供抗肥胖症的抗性。此外，含有SLN的染色体基因座的遗传改变也已被证明与人类的肥胖有关，表明SLN介导的能量消耗可能是肥胖症的一个因素。骨骼肌占哺乳动物体重的约40％，约占代谢底物消耗的80％。因此，骨骼肌为增加能量消耗提供了理想的目标，以药物为治疗肥胖症的策略。在此应用中，我建议使用多方面的方法，包括对整个动物，组织，细胞和计算水平的研究，以确定增强SLN介导的骨骼肌肉能量消耗的铅化合物。我有数据表明辣椒素可以增强SLN-serca结合。我还开发了一种基于细胞的测定，以筛选具有增强SLN介导的SERCA解偶联的能力的化合物。我通过修改侧链设计和合成了四个不同的辣椒素类似物。我的初步数据表明，这四个辣椒素 - 阿纳氏菌具有比辣椒素本身更好的活性。这些事实对我的最初假设提供了更大的信心，我提出了以下三个目标，以实现我的最终目标。在AIM 1中，我将尝试确定最佳的辣椒素 - 分析，以增加SLN介导的能量消耗和抗肥胖铅。在AIM 2中，我将进一步探索其他类型的化合物（校园的药学学院都可以使用许多化学图书馆），这些化合物可影响SERCA功能和/或增加能源消耗，以鉴定增加SLN介导的SERCA偶联并具有抗口感活性的化学物质。在AIM 3中，我正在努力开发一种SLN-Serca-s-配体相互作用的反应性原子模型，以定义药物团并优化入围的抗肥胖剂。我们认为，鉴定具有增强SLN对SERCA动作的能力的化学化合物将为药物增加基于肌肉的能量消耗和控制对象提供一个令人兴奋的新机会。