The goal of this project is to define the function of biologically important noncoding RNAs in Mycobacterium tuberculosis. It has recently become clear that noncoding RNAs play important regulatory roles in many prokaryotes. However, in Mtb, like most bacteria, the vast majority of them remain completely uncharacterized. We have experimentally identified over 1000 noncoding RNAs in Mtb, of which only 5 have been experimentally characterized to any extent. In this proposal, we will focus on one class of noncoding RNAs, trans-acting, intergenic regulatory RNAs, commonly termed small RNAs (sRNAs). While some sRNAs interact with and affect the function of proteins, the vast majority of sRNAs characterized to date influence the stability and/or translation of mRNAs. Thus, the critical steps in defining the biological function a regRNA are to identify the mRNA(s) it regulates and the biological consequences of this regulation?first at the level of the transcriptome and proteome (regulon) and then in terms of the cell's physiology. We propose a tiered series of aims in which we will define the function of candidate sRNAs with increasing specificity?first defining the importance of the candidates for Mtb growth under standard and

Public Health Relevance

Mycobacterium tuberculosis remains a catastrophic global health problem. In this proposal, we seek to define the function of a novel class of genes, regulatory RNAs, which have only recently been discovered in prokaryotes. We anticipate that the discoveries from these fundamental studies may ultimately lead to a better understanding of how to develop effective drugs and vaccines for tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI107774-01
Application #
8597703
Study Section
Special Emphasis Panel (ZAI1-FDS-M (M1))
Project Start
2013-07-02
Project End
2018-06-30
Budget Start
2013-07-02
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$287,071
Indirect Cost
$39,639
Name
Harvard University
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C (2016) Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr Opin Microbiol 29:30-6
Cheng, Yu-Shan; Sacchettini, James C (2016) Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance. Biochemistry 55:1107-19
Boutte, Cara C; Baer, Christina E; Papavinasasundaram, Kadamba et al. (2016) A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis. Elife 5:
Baric, Ralph S; Crosson, Sean; Damania, Blossom et al. (2016) Next-Generation High-Throughput Functional Annotation of Microbial Genomes. MBio 7:
Olive, Andrew J; Sassetti, Christopher M (2016) Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol 14:221-34
DeJesus, Michael A; Ioerger, Thomas R (2015) Capturing Uncertainty by Modeling Local Transposon Insertion Frequencies Improves Discrimination of Essential Genes. IEEE/ACM Trans Comput Biol Bioinform 12:92-102
Shell, Scarlet S; Wang, Jing; Lapierre, Pascal et al. (2015) Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape. PLoS Genet 11:e1005641
Long, Jarukit E; DeJesus, Michael; Ward, Doyle et al. (2015) Identifying essential genes in Mycobacterium tuberculosis by global phenotypic profiling. Methods Mol Biol 1279:79-95
Murphy, Kenan C; Papavinasasundaram, Kadamba; Sassetti, Christopher M (2015) Mycobacterial recombineering. Methods Mol Biol 1285:177-99
Baer, Christina E; Rubin, Eric J; Sassetti, Christopher M (2015) New insights into TB physiology suggest untapped therapeutic opportunities. Immunol Rev 264:327-43

Showing the most recent 10 out of 18 publications