Mycobacterium tuberculosis cell division and proliferation

结核分枝杆菌细胞分裂和增殖

• 批准号: 7795874
• 负责人: MALINI RAJAGOPALAN
• 金额: $ 33.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795874
• 关键词: Bacteria; Biochemical; Biological; Cell Cycle; Cell Division Process; Cell Wall; Cell division; Cells; Cessation of life; Chimeric Proteins; Disease; Environment; Funding; Genes; Genetic; Genome; Goals; Grant; Green Fluorescent Proteins; Growth; HIV; Homologous Gene; Hydrolase; Hypoxia; Immune; Immunity; In Vitro; Infection; Life Cycle Stages; Mediating; Molecular; Morbidity - disease rate; Multiprotein Complexes; Mycobacterium tuberculosis; Peptidoglycan; Physiological; Process; Proteins; Public Health; Regulation; Regulator Genes; Reporter; Role; Site; Source; Staging; Tuberculosis; Tubulin; adaptive immunity; base; in vivo; macrophage; mortality; novel; pathogen; polymerization; promoter; reactivation from latency; research study; response

DESCRIPTION (provided by applicant): Infections due to Mycobacterium tuberculosis (Mtb) are the leading causes of morbidity and mortality in both HIV infected and immune competent people. The hallmark of tuberculosis is latency, where bacteria are presumed to be metabolically active, but in a state of persistence. Cell division is a critical aspect of cell cycle, without which pathogen multiplication and subsequent infection does not ensue, and hence is expected to be regulated during 'entry into' and 'exit from' the persistent state. The genetic and biochemical aspects of cell division and the mechanisms used to regulate this process in Mtb at different stages of growth are largely unknown. The cell division process is believed to be mediated by several proteins that localize to the division site, and form a multiprotein complex called the septal ring. The initial step in the septal ring assembly appears to be the polymerization of a highly conserved tubulin-like protein, called FtsZ, in the form of a ring (Z-ring). Our recent studies indicate that Mtb growing in macrophages are filamentous and deficient for midcell Z-rings implying that Z-ring assembly and cell division are subject to regulation in vivo. One mode of regulation appears to involve targeting of a novel cell-wall hydrolase (CWH) activity encoded by Rv2719c (chiZ) to potential Z-ring assembly sites. Our proposal aims to investigate how Z-ring assembly and cell division are regulated during growth in vivo. We hypothesize that the intracellular milieu alters the expression and activities of unidentified FtsZ interaction partners and thereby modulates midcell Z-ring assembly and cell division. Using genetic, biochemical and cell biological approaches we propose to identify both the specific in vivo environment and the potential FtsZ interaction partners modulating midcell Z-ring assembly during intracellular growth. In vivo and in vitro interactions between putative regulators and FtsZ will be investigated in an effort to understand how Z-ring assembly is altered in response to infection. The biochemical activities and the potential mechanism of action of ChiZ in regulating Z-ring assembly, and therefore cell division, will be investigated. It is hoped that these experiments will define how the cell division process in Mtb is regulated and will advance our understanding of proliferation of Mtb in vivo.

描述(申请人提供)：结核分枝杆菌(结核分枝杆菌)感染是艾滋病毒感染者和有免疫能力的人发病和死亡的主要原因。结核病的特点是潜伏期，细菌被认为在代谢上是活跃的，但处于持续状态。细胞分裂是细胞周期的一个关键方面，如果没有分裂，病原体的繁殖和随后的感染就不会接踵而至，因此预计在进入和退出持续状态期间受到调节。细胞分裂的遗传和生化方面，以及在结核分枝杆菌不同生长阶段用于调节这一过程的机制，在很大程度上是未知的。细胞分裂过程被认为是由几种定位于分裂部位的蛋白质介导的，并形成了一种称为隔环的多蛋白质复合体。隔环组装的第一步似乎是高度保守的微管蛋白样蛋白FtsZ以环(Z环)的形式聚合。我们最近的研究表明，在巨噬细胞中生长的Mtb是丝状的，缺乏中细胞Z环，这意味着Z环的组装和细胞分裂在体内受到调节。一种调控模式似乎涉及将Rv2719c(Chiz)编码的一种新的细胞壁水解酶(CWH)活性靶向潜在的Z-环组装位点。我们的建议旨在研究Z环组装和细胞分裂是如何在体内生长过程中受到调控的。我们假设，细胞内环境改变了未知FtsZ相互作用伙伴的表达和活性，从而调节了中细胞Z环的组装和细胞分裂。利用遗传学、生化和细胞生物学方法，我们建议确定特定的体内环境和潜在的FtsZ相互作用伙伴，在细胞内生长过程中调节中细胞Z环组装。在体内和体外，将研究可能的调节子和FtsZ之间的相互作用，以努力了解Z环组装是如何在感染反应中改变的。我们将研究CHIZ在调节Z-环组装，从而调节细胞分裂中的生化活性和潜在的作用机制。希望这些实验将明确结核分枝杆菌的细胞分裂过程是如何调控的，并将促进我们对结核分枝杆菌体内增殖的理解。