. Biography . Publications . Staff . Links

David Sherman, Ph.D.

		Associate Member, Seattle Biomedical Research Institute Associate Professor, Department of Pathobiology,  University of Washington Email: david.sherman@sbri.org Disease under study: Tuberculosis

Mission
Dr. Sherman's work is focused on tuberculosis (TB) virulence and drug discovery. TB takes at least six months to treat, and the bacterium responsible has developed widespread resistance to the currently available drugs, so there is a great need for new therapies.

Research
With about one-third of the world population infected and two million deaths annually, Mycobacterium tuberculosis is unquestionably one of the world's most successful human pathogens. The Sherman laboratory studies the bacterial and host strategies that underpin this success. Dr. Sherman is especially interested in two formerly intractable areas of M. tuberculosis biology: virulence and dormancy.

Since roughly two billion people are infected with M. tuberculosis worldwide but only about 1% of those people have active disease, factors that alter the balance between latency and illness are of great interest. Dormant M. tuberculosis is thought to be associated with microaerophilic environments in the host, but current models to test this idea are inadequate. To address this situation, the Sherman lab has developed methods to maintain M. tuberculosis for extended periods in defined microaerophilic environments. Using this system, lab members have shown that the mycobacterial transcription factor DosR responds to a drop in oxygen tension by inducing expression of about 50 genes – the DosR regulon. They are performing detailed molecular characterization of hypoxic signal transduction and DosR activation.

The Sherman lab is also engaged in detailed analyses of M. tuberculosis gene expression in vitro and in vivo, and have developed a novel approach to study bacterial replication rate during infection. Lab members maintain a longstanding interest in what the TB vaccine BCG and other attenuated mutants can reveal about mycobacterial virulence. The lab is also interested in why TB treatment requires at least six months of chemotherapy.

The Sherman lab also focuses on novel assays and targets for much-improved anti-TB drugs and on understanding drug tolerance. Lab members routinely employ a variety of research tools, including molecular genetics (targeted gene disruption, representational difference analysis, TraSH), biochemistry, cultivation in vitro, in macrophages and in various animal models, and whole genome microarray analysis.

Themes
     *  TB virulence and dormancy
     *  Drug resistance and drug tolerance
     *  Development of new TB drugs

Accomplishments
      *  Helped to define the molecular and biochemical response of M. tuberculosis to oxidative stress and to drugs such as isoniazid
     *  Developed methods to maintain M. tuberculosis for extended periods in defined microaerophilic environments.
     *  Identified and characterized the M. tuberculosis response to reduced oxygen tension.
     *  Defined and characterized the molecular lesion responsible for attenuation of the TB vaccine, M. bovis BCG, which has been given to billions of people worldwide.

Collaborations
     *  University of Washington
     *  Harvard University
     *  National Institutes of Health
     *  Stanford University
     *  Imperial College, London
     *  University of Witwatersrand, Johannesburg

 Support for Dr. Sherman’s work is provided by the National Institutes of Health and by the Bill and Melinda Gates Foundation.
 

HOME | CONTACT US | SITEMAP | DONATE | POLICY

©2008 Seattle Biomedical Research Institute. All rights reserved.

SBRI is a 501(c)3 not-for-profit organization. info@sbri.org