Target Identification of Proteins and Peptides Capable of Recruitment of Brown Ad

能够招募棕色广告的蛋白质和肽的目标鉴定

• 批准号: 8646817
• 负责人: Olivier Boss
• 金额: $ 27.62万
• 依托单位: ENERGESIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646817
• 关键词: Adipocytes; Adult; Affect; Animal Model; Atrophic; Bioinformatics; Biological; Biological Assay; Body Temperature; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Differentiation process; Cells; Characteristics; Collection; Complementary DNA; Data; Desire for food; Development; Diabetes Mellitus; Dyslipidemias; Energy Intake; Energy Metabolism; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epidemic; Exposure to; Fatty acid glycerol esters; Gene Targeting; Genes; Glucose; Heating; Human; Individual; Lead; Maintenance; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Molecular Mechanisms of Action; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peptides; Phase; Play; Population; Positron-Emission Tomography; Proteins; Recruitment Activity; Resistance; Rodent; Rodent Model; Role; Serum; Skeletal Muscle; Stem cells; System; Systems Biology; Temperature; Testing; Therapeutic; Thermogenesis; Thinness; Time; Tissues; Venoms; Weight maintenance regimen; Weight-Loss Drugs; Work; animal efficacy; base; cell transformation; cold temperature; drug discovery; energy balance; flexibility; improved; in vivo; interest; knock-down; mitochondrial uncoupling protein; novel; overexpression; progenitor; public health relevance; receptor; small molecule; tool; uncoupling protein 1; weight maintenance

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. While most weight loss agents rely on suppressing appetite to reduce caloric intake, strategies that can safely enhance metabolic rate, a previously unrealized approach to weight loss or weight maintenance, have potential to effectively treat obesity. Brown adipocytes have an extremely high metabolic rate because they express mitochondrial uncoupling protein-1 (UCP1). This protein dissipates the electrochemical gradient in the mitochondria of brown adipocytes as heat. Brown adipose tissue (BAT) thermogenesis is increased upon exposure to low temperatures, and plays an important role in the maintenance of body temperature and energy balance in rodents. BAT is also a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, recent data obtained with PET imaging shows that adults in fact have significant BAT, and that this tissue is functional. Other data demonstrates that the amount of active BAT in individuals is strongly correlated with leanness. Until recently no brown adipocyte stem cell had been identified. We discovered a population of human skeletal muscle-resident brown adipocyte progenitors that under appropriate conditions become fully functional brown adipocytes. Following differentiation, these cells have high levels of UCP1 and a very high metabolic rate. Using the cells we developed a high-throughput phenotypic assay system to identify compounds that promote differentiation of the progenitors into mature, functional brown adipocytes. We have recently screened collections of human proteins as well as non-human biologicals, and have identified several compounds that strongly recruit brown adipocytes. Here we propose to study the molecular mechanisms of action of the hit compounds. We intend to use microarray transcriptional analysis with bioinformatics and systems biology to identify the pathways involved, followed by enzyme inhibitors and receptor panels to identify specific targets. If the mechanisms of these compounds are believed to be safe, these molecules or similar compounds with improved characteristics could be developed as therapeutics for obesity and/or diabetes. The targets may also serve as the basis for small molecule drug discovery. If the Phase I project is successful, we plan to subsequently advance into animal efficacy studies. Compounds will be synthesized in amounts sufficient for in vivo testing, serum stability will be evaluated, and the compounds will then be studied in appropriate animal models of obesity and type 2 diabetes.

描述（由申请人提供）：肥胖在美国已达到流行病的比例，并在2型糖尿病、血脂异常和心血管疾病的发展中起主要作用。虽然大多数减肥药依赖于抑制食欲来减少热量摄入，但可以安全地提高代谢率的策略，这是一种以前未实现的减肥或维持体重的方法，具有有效治疗肥胖的潜力。棕色脂肪细胞具有极高的代谢率，因为它们表达线粒体解偶联蛋白-1（UCP 1）。这种蛋白质将棕色脂肪细胞线粒体中的电化学梯度作为热量消散。棕色脂肪组织（BAT）产热在低温下增加，在维持啮齿动物体温和能量平衡中起重要作用。BAT也是一种柔性组织，通常会随着时间的推移而扩大或萎缩，这取决于环境温度。在许多不同的啮齿动物模型中，BAT质量的增加已经令人信服地显示出导致体重减轻和糖尿病抵抗。虽然BAT直到最近才被认为在成年人中实际上不存在，但最近通过PET成像获得的数据显示，成年人实际上具有显著的BAT，并且该组织具有功能。其他数据表明，个体中活跃BAT的数量与瘦度密切相关。直到最近还没有发现棕色脂肪干细胞。我们发现了一群人类骨骼肌驻留的棕色脂肪细胞祖细胞，在适当的条件下成为功能齐全的棕色脂肪细胞。分化后，这些细胞具有高水平的UCP 1和非常高的代谢率。使用这些细胞，我们开发了一种高通量表型测定系统，以鉴定促进祖细胞分化为成熟的功能性棕色脂肪细胞的化合物。我们最近筛选了人类蛋白质和非人类生物制品的集合，并确定了几种强烈招募棕色脂肪细胞的化合物。在这里，我们建议研究命中化合物的分子作用机制。我们打算使用微阵列转录分析与生物信息学和系统生物学，以确定所涉及的途径，其次是酶抑制剂和受体面板，以确定特定的目标。如果这些化合物的机制被认为是安全的，则这些分子或具有改进特性的类似化合物可以被开发为肥胖症和/或糖尿病的治疗剂。这些靶点也可以作为小分子药物发现的基础。如果第一阶段项目成功，我们计划随后进入动物功效研究。化合物将以足以用于体内测试的量合成，将评价血清稳定性，然后将在适当的肥胖症和2型糖尿病动物模型中研究化合物。