Chemical Inhibitors to Define an Essential M. Tuberculosis Signaling Network

化学抑制剂定义重要的结核分枝杆菌信号网络

• 批准号: 8666913
• 负责人: ROBERT N HUSSON
• 金额: --
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2013-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666913
• 关键词: Accounting; Anabolism; Antitubercular Agents; Area; Carbon; Cell Wall; Cell division; Cells; Cellular biology; Chemicals; Clinical; Computational Biology; Computing Methodologies; Data; Development; Disease; Drug Resistant Tuberculosis; Drug Targeting; Enzyme Inhibition; Enzymes; FDA approved; Future; Genes; Genetic; Genome; Goals; Growth; Human; In Vitro; Individual; Investigation; Investments; Knowledge; Lipids; Malignant Neoplasms; Measures; Metabolism; Methodology; Molecular Biology; Morbidity - disease rate; Mycobacterium tuberculosis; Mycolic Acid; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Physiological; Physiological Processes; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Proteome; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Staging; System; Transcript; Translating; Trehalose; Tuberculosis; Validation; antimicrobial; antimicrobial drug; base; biological adaptation to stress; cancer therapy; cell envelope; drug development; genetic regulatory protein; glucose mycolate; inhibitor/antagonist; insight; kinase inhibitor; lipid biosynthesis; metabolomics; mortality; mycolate; network models; novel; pathogen; physiologic model; research and development; research clinical testing; research study; response; screening; small molecule; structural biology; success; tool; transcriptomics; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): In response to RFA-AI-11-004, this application proposes a highly collaborative research plan to use small molecule chemical inhibitors as probes to characterize the physiologic processes in Mycobacterium tuberculosis that are regulated by the essential Serine/Threonine protein kinases PknA and PknB. These kinases are both candidate drug targets themselves, and regulate downstream proteins and pathways that will also be potential targets for drug development. The PI and co-investigators will bring together state of the art expertise in transcriptomics, phosphoproteomics, lipidomics, metabolomics and computational biology with the goal of achieving a systems-level understanding of the PknA/PknB signaling network. In addition to this multi-platform "omics" approach, an important strength of the proposal is the use in this research of novel highly potent chemical inhibitors of these kinases as probes for PknA/PknB-regulated networks. The research proposes both unbiased, broad approaches to identify processes regulated by these kinases, and targeted approaches focused on two essential cell envelope biosynthetic pathways for which substantial data indicates a regulatory role for PknA and PknB: peptidoglycan synthesis and mycolic acid synthesis. While each research platform will generate data that will provide direct insight into the functions of PknA and PknB, another key component of this approach is to use computational methods to model networks that integrate the different types of experimental data. The results of this research will provide systems-level insights into the PknA/PknB signaling pathways and the processes that they regulate. We expect this knowledge will validate these kinases as excellent targets for M. tuberculosis drug development and identify proteins and processes regulated PknA and PknB that may also be attractive targets for anti-tuberculosis drug development.

描述（由申请人提供）：针对 RFA-AI-11-004，本申请提出了一项高度协作的研究计划，使用小分子化学抑制剂作为探针来表征结核分枝杆菌中受必需丝氨酸/调节的生理过程。苏氨酸蛋白激酶 PknA 和 PknB。这些激酶本身都是候选药物靶点，并调节下游蛋白质和途径，这些也将成为药物开发的潜在靶点。 PI 和联合研究人员将汇集转录组学、磷酸蛋白质组学、脂质组学、代谢组学和计算生物学领域最先进的专业知识，目标是实现对 PknA/PknB 信号网络的系统级理解。除了这种多平台“组学”方法之外，该提案的一个重要优势是在本研究中使用这些激酶的新型高效化学抑制剂作为 PknA/PknB 调节网络的探针。该研究提出了两种公正、广泛的方法来识别这些激酶调节的过程，以及专注于两种重要的细胞包膜生物合成途径的针对性方法，大量数据表明 PknA 和 PknB 的调节作用：肽聚糖合成和分枝菌酸合成。虽然每个研究平台都会生成可以直接洞察 PknA 和 PknB 功能的数据，但该方法的另一个关键组成部分是使用计算方法来对集成不同类型实验数据的网络进行建模。这项研究的结果将为 PknA/PknB 信号通路及其调节过程提供系统级的见解。我们期望这些知识将验证这些激酶作为结核分枝杆菌药物开发的优秀靶点，并确定 PknA 和 PknB 调节的蛋白质和过程，它们也可能是抗结核药物开发的有吸引力的靶点。