HTS for Modulators of MitoNEET Proteins' Function

描述(申请人提供)：全球肥胖率的上升与肥胖相关疾病的急剧增加同步，最明显的是II型糖尿病。据预测，这种疾病在未来几十年内将达到流行的程度。因此，了解II型糖尿病潜在的生化过程并确定新的治疗干预目标对国家和世界健康至关重要。一些最广泛用于治疗II型糖尿病的胰岛素增敏药物属于噻唑烷二酮(TZD)类分子。这些药物被发现还可以减少与代谢综合征相关的许多病理疾病，包括高血压、腹型肥胖、冠状动脉炎症、多发性硬化症、阿尔茨海默病和肌萎缩侧索硬化症。虽然TZD最初被认为仅通过激活核转录因子PPAR？发挥其作用，但已知许多有益的影响是以PPAR？不依赖的方式介导的。TZD最近被证明与一种名为mitoNEET的新型线粒体蛋白靶标相互作用。我们报道了mitoNEET蛋白是一个氧化还原活性的、pH不稳定的2Fe-2S簇，含有位于线粒体膜外的蛋白。这是线粒体膜外膜中唯一已知的铁-S蛋白。Miner1是mitoNEET的内质网同系物，在维持健康和长寿方面非常重要，并与癌症和神经退行性疾病相关的蛋白质相互作用。这些蛋白质已经成为从糖尿病到阿尔茨海默氏症等疾病的重要新治疗靶点。这项建议的重点是实施高通量筛选方法，首先识别调节这个新蛋白质家族活性的小分子，然后在二次筛选方法中验证已识别的靶点，利用这些研究获得的知识开发潜在的治疗方法，并在细胞分析中测试已识别的分子的效果。

DESCRIPTION (provided by applicant): The rise in obesity worldwide parallels a dramatic increase in obesity-associated diseases, most notably type-II diabetes. This disease is predicted to reach epidemic proportions in the next several decades. Thus, understanding the biochemical processes underlying type-II diabetes and identifying new targets for therapeutic intervention are critical for national and world health. Some of the most widely prescribed insulin-sensitizing drugs to treat type-II diabetes belong to the thiazolidinedione (TZD) class of molecules. These drugs were found to also reduce many of the pathologies related to metabolic syndrome including hypertension, abdominal obesity, coronary artery inflammation, multiple sclerosis, Alzheimer's disease and Amyotrophic lateral sclerosis. While the TZDs were originally thought to exert their effects solely through activation of the nuclear transcription factor PPAR¿, it is nw known that many of the beneficial effects are mediated in a PPAR¿-independent manner. The TZDs were recently shown to interact with a novel mitochondrial protein target called mitoNEET. We reported that the protein mitoNEET is a redox-active, pH-labile 2Fe-2S cluster containing protein in the outer mitochondrial membrane. This is the only known Fe-S protein in the outer- mitochondrial membrane. Miner1, an endoplasmic reticulum homolog of mitoNEET, is important in maintaining health and longevity and interacts with proteins associated with cancer as well as neurodegenerative diseases. These proteins have emerged as important new therapeutic targets in diseases ranging from diabetes to Alzheimer's. The focus of this proposal is to implement high through-put screening methods to first identify small molecules that modulate the activity of this novel protein family, second validate the identified targets in secondary screening methods, use the knowledge gained from these studies to develop potential therapeutics and test the effects of identified molecules in cellular assays.