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: 10341223
• 负责人: Gloria Marcela Rodriguez
• 金额: $ 19.63万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341223
• 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.

概括 结核病（TB）是全球一个重大的公共卫生问题。虽然死亡人数 由于诊断和早期治疗的改善，近年来结核病已减少， 抗生素耐药性的持续增加以及新的有效药物的短缺 结核分枝杆菌有可能破坏结核病控制工作。我们的研究重点 利用结核分枝杆菌（MTB）对铁失调的敏感性产生新的治疗性 防止MTB毒力和增强抗生素作用的策略。 铁是结核分枝杆菌所需的必不可少的微量营养素才能建立生产性感染。 但是，由于这种金属的倾向催化了铁可能非常毒性 活性氧的产生，可能会损害所有大分子。像所有铁一样 依赖性细胞，MTB必须平衡细胞内铁的水平，因为它遇到多种铁 主机中的环境。来自动物研究的证据表明维持铁的能力 稳态对于MTB增殖和引起疾病至关重要。反过来，我们以前的研究 确定MTB取决于全球转录调节器IDER来控制铁 稳态。 我们的初步研究表征了能够诱导的自然反义转录本（IDER-AS） 在MTB中反式表达时铁失调。尽管此RNA改变了 由IDER控制的基因，它似乎不是通过改变IDER级别及其作用方式来起作用 不了解。我们假设IDER-AS AS调节IDER活动。我们为此目标 提案将调查IDER-AS AS行动方式，并评估IDER-AS之间的协同作用 和抗生素。我们希望解密该RNA如何影响铁调节将指导 旨在针对MTB的铁稳态的努力。