Drug Target Discovery in Obesity Neurons

在过去的十年中，肥胖研究的关键进展已经确立了中枢神经系统(CNS)在体重调节中的重要性。这项拟议研究的目标是开发一种靶标发现方法，该方法将挖掘已知表达重要肥胖基因的中枢神经系统中的神经元。这一目标将使用最近开发的最先进的技术来实现，从完整的大脑中进行基因标记，然后从已知对体重调节重要的特定神经元亚型中分离出来。然后，我们将对这些“肥胖神经元”的转录组进行分类，并确定这些神经元在旨在揭示基因功能的条件下的基因表达谱。在特定神经元亚型中选择性表达的基因的鉴定将为下一代抗肥胖药物靶点提供分子原料。提出的中枢神经系统靶标发现方法结合了三项核心技术：(1)利用改进的细菌人工染色体(BAC)转基因对神经元亚群进行遗传标记；(2)获取标记的“肥胖神经元”；(3)在旨在揭示基因功能的条件下，对捕获的“肥胖神经元”进行RNA表达谱分析。最终的商业目标是销售或许可经过验证的中枢神经系统减肥药物靶标、靶标特定的高通量分析以及这些靶标的化学先导。拟议的商业应用：本研究衍生的优化药物发现平台将成为识别各种中枢神经系统药物靶点的标准化方法，而不仅仅是与肥胖有关的药物靶点。该平台的商业价值将通过靶标的质量和针对这些靶标开发的潜在化学铅来实现。

Key advances in obesity research over the last decade have established the prominence of the central nervous system (CNS) in body weight regulation. The goal of the proposed research is to develop a target discovery approach that will mine neurons in the CNS known to express important obesity genes. This goal will be accomplished using recently-developed state-of-the-art techniques to genetically tag and then isolate, from the intact brain, specific neuronal subtypes already known to be important for body weight regulation. We will then catalog the transcriptome of these "obesity neurons" and determine gene expression profiles of these neurons under conditions designed to reveal gene function. The identification of genes selectively expressed in specific neuronal subtypes will provide the molecular raw material for the next generation of anti-obesity drug targets. The proposed approach for CNS target discovery combines three core technologies: (1) genetic tagging of neuronal subpopulations with modified bacterial artificial chromosome (BAC) transgenes, (2) harvesting of tagged "obesity neurons" and (3) RNA expression profiling analysis of the captured "obesity neurons" under conditions designed to reveal gene function. The ultimate commercial aim is to sell or license validated CNS anti-obesity drug targets, target-specific high through-put assays, and chemical leads for these targets. PROPOSED COMMERCIAL APPLICATION: The optimized drug discovery platform derived from this research will serve as a standardized method for identifying various CNS drug targets, not only those involved in obesity. The commercial value of the platform will be realized through the quality of targets and by the potential chemical leads developed against these targets.