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

描述(申请人提供)：肥胖症在美国已经达到流行的程度，并在2型糖尿病、血脂异常和心血管疾病的发展中起着重要作用。虽然大多数减肥剂依赖于抑制食欲来减少卡路里摄入量，但可以安全地提高代谢率的策略，一种以前没有实现的减肥或减肥方法，有可能有效地治疗肥胖症。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(UCP1)。这种蛋白质以热的形式驱散棕色脂肪细胞线粒体中的电化学梯度。棕色脂肪组织(BAT)在低温环境下产热增加，对维持啮齿动物的体温和能量平衡起着重要作用。蝙蝠也是一种柔韧的组织，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，蝙蝠质量的增加已被令人信服地证明可以导致体重减轻和糖尿病抵抗。虽然直到最近，人们还认为成年人中实际上不存在蝙蝠，但最近通过PET成像获得的数据表明，成年人实际上有重要的蝙蝠，而且这个组织是有功能的。其他数据表明，个体中活跃的蝙蝠数量与苗条程度密切相关。直到最近，还没有发现棕色脂肪干细胞。我们发现了一组人类骨骼肌中的棕色脂肪细胞前体细胞，在适当的条件下，它们会变成功能齐全的棕色脂肪细胞。分化后，这些细胞具有高水平的UCP1和非常高的代谢率。利用这些细胞，我们开发了一种高通量的表型分析系统，以鉴定促进祖细胞分化为成熟的、功能正常的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，并鉴定了几种强烈招募棕色脂肪细胞的化合物。在这里，我们打算研究HIT化合物的分子作用机制。我们打算使用生物信息学和系统生物学的微阵列转录分析来确定涉及的途径，然后使用酶抑制剂和受体面板来确定特定的靶点。如果这些化合物的机制被认为是安全的，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/或糖尿病的治疗药物。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。化合物的合成数量将足以进行体内测试，血清稳定性将得到评估，然后这些化合物将在适当的肥胖和2型糖尿病动物模型中进行研究。

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.