Scripps Research Institute Molecular Screen Center(RMI)

描述（由申请人提供）：MLSCN提案的关键假设是高通量化学方法，当与最先进的后基因组序列，细胞，分子和体内生物学相结合时，通过发现概念验证（POC）分子，为促进生物医学科学的进步提供了一种快速简便的机制。此外，它的POC分子的发现将显著加快生物医学进步的应用，以提高公众健康和生活质量。在过去的两年中，TSRI和其他地方的实验工作提供了大量同行评议的论文，这些论文支持这些方法快速推动领域发展的能力。此外，他们举例说明了一个良好的集成过程的能力，以发现精细的选择性，效力和体内功效的化学探针分子，并确定新的生物靶标。当现代高通量化学生物学可以与遗传方法相结合时，例如同源重组靶基因的缺失，或具有显着体外活性的化合物的表达谱，就会出现令人信服的结果。这些方法为淋巴细胞再循环和免疫抑制的调节以及神经发生的生物控制确定了新的关键点。TSRI的分析专业知识涵盖了许多不同的格式，从全细胞钙通量分析，报告基因分析，酶分析，蛋白质蛋白质相互作用和细胞分化读数。我们进一步期望这种方法与更高通量的分子生物学方法（如siRNA）协同作用，从而成为后基因组序列生物医学科学的科学动力的基本驱动因素。因此，TSRI提案的主题是灵活的，跨目标类别的概念验证分子的综合发现，重点是gpcr和细胞分化途径。我们建议通过具体承诺这三个具体目标来实现这一点：目标#1：建立一个能够在第2年和第3年每年优化20个检测的检测实施小组。目标2：实施HTS，每年筛选20种分析，每次分析至少筛选100,000种化合物，并及时将有质量保证的数据转移到PubChem数据库。目标#3：开发药代动力学和探索性合成化学基础设施，以识别能够在基于细胞的系统或体内进行生物概念验证（POC）的命中或命中衍生分子。这些目标的实施将为将化学生物学工具传播到更广泛的生物医学研究领域提供社区数据、工具和资源，从而增强NIH人类健康可测量终点路线图的成功和影响。

DESCRIPTION (provided by applicant): The key hypothesis of the MLSCN proposal is that high throughput chemical approaches, when integrated with state-of-the art post-genome sequence, cell, molecular and in vivo biology, provides a rapid and facile mechanism for enhancing the progress of biomedical science by the discovery of proof-of-concept (POC) molecules. Moreover, it POC molecule discovery will significantly speed up the application of biomedical advances to enhancing the public health and quality of life. Experimental efforts at TSRI and elsewhere have provided substantial peer-reviewed papers over the past 2 years that support the ability of these approaches to move fields forward with great rapidity. In addition, they exemplify the ability of a well integrated process to discover chemical probe molecules of exquisite selectivity, potency and in vivo efficacy, and to define novel biological targets. Compelling results emerge when modern high throughput chemical biology can be integrated with genetic approaches such as homologous recombinant deletion of target genes, or expression profiling of compounds with significant in vitro activity. These approaches have defined new key points of biological control in the regulation of lymphocyte recirculation and immunosuppression, as well as in neurogenesis. Assay expertise within TSRI has covered many different formats from whole cell calcium flux assays, reporter gene assays, enzyme assays, protein-protein interactions and cellular differentiation readouts. We further expect this approach to synergize with higher throughput molecular biological approaches such as siRNA, and therefore be a fundamental driver for scientific momentum in post-genome sequence biomedical science. The theme of the TSRI proposal is therefore the flexible, integrated discovery of proof-of-concept molecules across target classes, with an emphasis on GPCRs and pathways of cellular differentiation. We propose to do so by committing specifically to these three Specific Aims: Aim #1: Establish an Assay Implementation Group with the ability to optimize 20 assays per year during Years 2 and 3. Aim #2: Implement HTS to screen 20 assays and a minimum of 100,000 compounds per assay per year with transfer of the quality-assured data in a timely matter to PubChem database. Aim #3: development of pharmacokinetics and exploratory synthetic chemistry infrastructure to identify hits or hit-derived molecules capable of allowing biological proof of concept (POC) in cell-based systems or in vivo. Execution on these goals will provide community data, tools and resources for the dissemination of the tools of chemical biology to a broader segment of the biomedical research, thus enhancing the success and impact of the NIH Roadmap of measurable endpoints in human health.