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（由申请人提供）：肥胖是美国的一个主要健康问题，据报道，2010 年仅因肥胖造成的累计健康成本就达到约 800 亿美元，预计到 2025 年将超过 3500 亿美元过去二十年的研究表明，在大多数情况下，肥胖是由于能量过剩造成的，并且可以通过增加能量消耗来治疗，尽管在了解针对细胞生物能量学的方法方面取得了重大进展。增加能量消耗其中大部分依赖于基于解偶联蛋白 1 (UCP1) 的机制，该机制是大多数成年人的次要组成部分，因此，应同等重视增加生热作用的机制来治疗肥胖。最近，我们发现了一种名为肌脂蛋白 (SLN) 的蛋白质的新型生热机制，该机制于 2012 年发表在《自然医学》杂志上。SLN 是一种 31 个氨基酸的单跨膜蛋白，可调节 SERCA 泵的功能。 SLN 与 SERCA 的结合促进 SERCA 泵的 ATP 水解与 Ca2+ 运输脱钩，导致无效循环，并增加 ATP 利用率，从而促进基于肌肉的非颤抖产热 (NST)。脂肪饮食（HFD）但 SLN 的上调可以预防 HFD 诱导的肥胖，我们的下一项研究表明，骨骼肌特异性的 SLN 过度表达可驱动线粒体生物发生。并促进骨骼肌的氧化代谢，从而抵抗肥胖，该研究正处于出版的最后阶段。此外，含有 SLN 的染色体位点的基因改变也已被证明与人类肥胖有关，这表明 SLN 介导的能量消耗可能是一个因素。在肥胖症中，骨骼肌约占哺乳动物体重的 40%，占代谢底物消耗的约 80%，因此从药理学角度来看，骨骼肌是增加能量消耗的理想目标。在这个应用中，我建议使用多方面的方法，包括在整个动物、组织、细胞和计算水平上的研究，来识别铅增强化合物 SLN 介导的基于骨骼肌的能量消耗。我还开发了一种基于细胞的测定法来筛选能够增强 SLN 介导的 SERCA 解偶联的化合物。我设计并合成了四种不同的辣椒素类似物。我的初步数据表明，这四种辣椒素类似物具有比辣椒素本身更好的活性，这些事实为我的最初假设提供了更多信心，并且我在目标 1 中提出了以下三个目标：我将尝试找出最佳的辣椒素类似物来增加 SLN 介导的能量消耗和抗肥胖作用。在目标 2 中，我将进一步探索其他类别的化合物（药学院有许多化学库可供使用）。校园）已知会影响 SERCA 功能和/或增加能量消耗，以识别增加 SLN 介导的 SERCA 解偶联并具有抗肥胖活性的化学物质。在 AIM 3 中，我正在努力开发 SLN-SERCA 的响应原子模型。我们相信，鉴定能够增强 SLN 对 SERCA 作用的化合物将为药理学增强提供令人兴奋的新机会。基于肌肉的能量消耗和控制肥胖。