权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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