This proposal describes a five year research career development program in the study of Mycobacterium tuberculosis (M. tuberculosis) pathogenesis. The candidate is training in Infectious Diseases. The outlined proposal will provide training in the use of forward chemical genetics as a tool for studying mechanisms of microbial pathogensis and the host immune response, in preparation for a career as an independent physician-scientist in the field of M. tuberculosis pathogenesis and the host-pathogen interface. The work will be conducted under the mentorship of Dr. Deborah Hung, Assistant Professor of Microbiology and Molecular Genetics and Harvard Medical School, and Dr. Eric Rubin, Associate Professor of Immunology and Infectious Disease at Harvard School of Public Health. M. tuberculosis remains a major cause of morbidity and mortality globally. A detailed understanding of molecular mechanisms of M. tuberculosis virulence would offer insight into new approaches to the treatment of tuberculosis. Upon entering the human host, M. tuberculosis is quickly taken up into macrophages, where it successfully evades being killed and establishes a chronic form of infection. The mechanisms by which it subverts macrophage pathways for eliminating intracellular bacteria are not well-described. Forward chemical genetics is a potentially powerful tool to advance our knowledge of manipulation of macrophage biology by M. tuberculosis. This proposal outlines a plan to to investigate the details of interactions between host macrophages and M. tuberculosis using both a forward chemical genetic and a classical genetic approach. It is anticipated that a better understanding of molecular details of M. tuberculosis virulence will offer new potential targets for the development of future therapeutics. Tuberculosis remains an important threat to health globally. Our current medications are inadequate to face the growing problems of tuberculosis and drug-resistant tuberculosis. This proposal aims to enhance our understanding of infection, to offer new possibilities for future treatment development.

Public Health Relevance

Tuberculosis remains an important threat to health globally. Our current medications are inadequate to face the growing problems of tuberculosis and drug-resistant tuberculosis. This proposal aims to enhance our understanding of infection, to offer new possibilities for future treatment development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI080944-03
Application #
8318274
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Jacobs, Gail G
Project Start
2010-09-29
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$137,085
Indirect Cost
$9,710
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Stanley, Sarah A; Barczak, Amy K; Silvis, Melanie R et al. (2014) Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth. PLoS Pathog 10:e1003946
Barczak, Amy K; Gomez, James E; Kaufmann, Benjamin B et al. (2012) RNA signatures allow rapid identification of pathogens and antibiotic susceptibilities. Proc Natl Acad Sci U S A 109:6217-22