Investigation of the mechanisms and effects of riboregulation of iron homeostasis in M. tuberculosis

结核分枝杆菌铁稳态核糖调节机制和影响的研究

• 批准号: 10190035
• 负责人: Gloria Marcela Rodriguez
• 金额: $ 23.49万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-04 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190035
• 关键词: Affect; Animals; Antibiotic Resistance; Antibiotics; Antisense RNA; Antitubercular Agents; Biochemical; Cells; Cessation of life; Coenzymes; Data; Diagnostic; Disease; Early treatment; Enhancers; Environment; Equilibrium; Gene Expression; Genes; Genetic; Genetic Transcription; Genus Mycobacterium; Goals; Homeostasis; In Vitro; Infection; Investigation; Iron; Knowledge; Life; Mediating; Metals; Micronutrients; Mutate; Mycobacterium tuberculosis; Organism; Oxidative Stress; Pathogenesis; Pharmaceutical Preparations; Phenotype; Production; Proliferating; Proteins; Public Health; RNA; Reactive Oxygen Species; Regulation; Research; Testing; Therapeutic Human Experimentation; Toxic effect; Transcript; Translating; Tuberculosis; Virulence; Virulent; Work; comparative; derepression; design; effectiveness evaluation; improved; in vivo; interest; iron metabolism; isoniazid; knock-down; macromolecule; macrophage; mutant; novel therapeutic intervention; novel therapeutics; overexpression; prevent; synergism; therapeutically effective; tool; toxic metal; transcriptomics; tuberculosis treatment; uptake

Summary Tuberculosis (TB) is a significant public health problem worldwide. Although the number of deaths due to TB has decreased in recent years thanks to improved diagnostics and early treatment, the sustained increase in antibiotic resistance and the shortage of new effective drugs against Mycobacterium tuberculosis threatens to undermine TB control efforts. Our studies focus on exploiting M. tuberculosis (Mtb) sensitivity to iron dysregulation to generate new therapeutic strategies that prevent Mtb virulence and potentiate antibiotic action. Iron is an essential micronutrient required by M. tuberculosis to establish a productive infection. However, excess iron can be very toxic due to the propensity of this metal to catalyze the production of reactive oxygen species, which can damage all macromolecules. Like all iron- dependent cells, Mtb must balance intracellular iron levels as it encounters diverse iron environments in the host. Evidence from animal studies indicates that the ability to maintain iron homeostasis is essential for Mtb to proliferate and cause disease. In turn, our previous studies established that Mtb depends on the global transcriptional regulator, IdeR, to control iron homeostasis. Our preliminary studies characterized a natural antisense transcript (IdeR-AS) capable of inducing iron dysregulation when expressed in trans in Mtb. Although this RNA alters the expression of genes controlled by IdeR, it does not seem to act by altering IdeR levels, and its mode of action is not understood. We hypothesize that IdeR-AS modulates IdeR activity. Our goals for this proposal are to investigate IdeR-AS mode of action and evaluate the synergy between IdeR-AS and antibiotics. We expect that deciphering how this RNA influences iron regulation would guide efforts to target iron homeostasis in Mtb.

总结 结核病（TB）是一个全球性的重大公共卫生问题。虽然死亡人数 近年来，由于诊断和早期治疗的改善， 抗生素耐药性持续增加，缺乏新的有效药物， 结核分枝杆菌威胁着结核病控制工作。我们的研究集中在 利用M.结核病（Mtb）对铁失调的敏感性，以产生新的治疗方法 预防Mtb毒力和增强抗生素作用的策略。 铁是M.结核病建立生产性感染。 然而，过量的铁可能是非常有毒的，因为这种金属倾向于催化铁的氧化。 产生活性氧，这可能会破坏所有的大分子。就像所有的铁- 依赖细胞，结核分枝杆菌必须平衡细胞内的铁水平，因为它遇到不同的铁 环境中的主机。动物研究的证据表明，维持铁的能力 稳态对于结核分枝杆菌增殖和引起疾病是必不可少的。反过来，我们以前的研究 确定Mtb依赖于全局转录调节因子IdeR来控制铁 体内平衡 我们的初步研究特征在于天然反义转录物（IdeR-AS）能够诱导 当在Mtb中反式表达时，铁失调。尽管这种RNA改变了 在IdeR控制的基因中，它似乎不通过改变IdeR水平起作用， 不被理解。我们假设IdeR-AS调节IdeR活性。我们的目标 建议是调查IdeR-AS的作用模式，并评估IdeR-AS之间的协同作用 和抗生素。我们希望，破译这种RNA如何影响铁的调节将指导 在结核病中靶向铁稳态的努力。