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Accession Number:
AD1064876
Title:
Establishing Sts-1 as a Novel Target to Treat Deadly Pathogen Infections
Report Date:
2018-06-01
Abstract:
This proposal addresses a unique approach to improving clinical outcomes for individuals who have contracted life-threatening bacterial and fungal infections. Two homologous phosphatases, Sts-1 and Sts-2, have been established as negative regulators of signaling pathways within mammalian immune cells. Experimental mice in which the Sts proteins are functionally inactivated have been shown to be profoundly resistant to infection with high doses of different microbial pathogens, including Candida albicans, Francisella tularensis LVS, and Staphylococcus aureus. Resistance was characterized by an altered immune response and enhanced pathogen clearance. We propose to develop pharmacological inhibitors of Sts-1, in order to enhance anti-microbial immune responses. Proposed aims are to 1) determine how leukocyte anti-microbial effector functions are regulated by Sts-1 activity; 2) conduct a 20,000 compound pilot screen for Sts-1 inhibitors; 3) solve X-ray crystal structures of Sts-1-drug complexes to characterize the active site architecture; and 4) assess how HTS lead compounds alter leukocyte microbicidal responses and survival curves following infection.
Document Type:
Conference:
Journal:
Pages:
84
File Size:
9.24MB
W81XWH-17-1-0147, PR161377
(W81XWH1710147, PR161377);
Contracts:
Grants:
Distribution Statement:
Approved For Public Release
