Regulation of Cellular division in M. tuberculosis

描述（由申请人提供）： 本提案是对PA-01-113“艾滋病相关的结核病感染和恶性肿瘤的治疗研究”的回应，并特别针对结核分枝杆菌（MTB）的研究。该提案的主旨是开发新的药物靶点，以对抗多种耐药生物。该研究计划的长期目标是开发新型化疗药物，靶向MTB中染色体分离和细胞分裂的调节和协调。为此，我们已经在MTB基因组中鉴定了与其他原核生物中与这些过程相关的蛋白质同源的基因产物。此外，我们的初步结果提供了强有力的证据，这些基因产物（FtsZ和Ftsl同源物）积极参与MTB的细胞分裂。然而，需要对这些基因产物进行更广泛的分析，并对参与MTB细胞分裂的潜在调控网络进行全面评估。与新月柄杆菌的工作类似，我们假设用MTB的同步培养物进行DNA微阵列分析将使我们能够在该细菌的整个细胞分裂周期中开发基因表达谱的详细模式。此外，使用已知的细胞分裂早期（FtsZ活性）和晚期（Ftsl活性）事件的抑制剂沿着全球基因表达研究将进一步阐明在细胞分裂的不同阶段激活的调控网络。通过基因表达谱分析，对已经确定的和新阐明的推定调控基因进行最终分析，将使我们能够详细了解MTB细胞分裂的调控网络和时间基因表达。这些研究将确保未来的资源很好地针对适当的化疗目标和开发合适的药物发现策略。因此，本申请中提出的研究旨在检查MTB的复制动力学，特别关注参与细胞分裂的细胞周期调节基因。

DESCRIPTION (provided by applicant): This Proposal is in response to PA-01-113, "Therapeutics Research on AIDS-Associated Opportunistic Infections and Malignancies" and specifically addresses the study of Mycobacterium tuberculosis (MTB). The thrust of this proposal is the development of novel drug targets to counteract multiple drug resistant organisms. The long-term goal of this research program is to develop novel classes of chemotherapeutics that target the regulation, and coordination of chromosomal segregation and cellular division in MTB. Toward this objective we have identified in the MTB genome, gene products that are homologous to proteins associated with these processes in other prokaryotes. Moreover, our preliminary results provide strong evidence that some of these gene products (FtsZ and Ftsl homologues) actively participate in the cellular division of MTB. However, a more extensive analysis of these gene products and global assessment of the potential regulatory networks involved in the division of MTB cells are required. Similar to work with Caulobacter crescentus we hypothesize that DNA microarray analysis with synchronized cultures of MTB will allow us to develop a detailed pattern of gene expression profiles across the entire cell division cycle of this bacterium. Additionally, the use of known inhibitors of early (FtsZ activity) and late (Ftsl activity) events of cell division along with global gene expression studies will further elucidate the regulatory networks that are activated during different stages of cell division. A final analysis of putative regulatory genes already identified and new ones elucidated through gene expression profiling will enable us to develop a detailed picture of the regulatory networks and temporal gene expression responsible for MTB cellular division. Such studies will ensure that future resources are well directed at appropriate chemotherapeutic targets and developing suitable drug discovery strategies. Thus, the studies proposed in this application are designed to examine the replication dynamics of MTB, specifically focusing on cell cycle-regulated genes that are involved in cell division.