The primary research goals of this Mentored Research Scientist Development Award proposal are to study the mechanisms by which types I and III interferon (IFN) cooperate to resolve hepatitis C virus (HCV) infection. Despite the ubiquitous use of IFN? for treatment of HCV infection, its mechanisms of action are poorly understood. The research plan is partly based on previous screening efforts by the candidate to identify and characterize type I IFN- stimulated genes (ISGs) with previously unknown antiviral activities. Additionally, with the recent discovery that genetic variation in IL28B (a type III IFN is associated with treatment-induced HCV clearance, new models have emerged suggesting a functional interdependence of these two IFN systems. The experimental aims are designed to test these models in the context of clinically- meaningful outcomes. The effects of IL28B genotype on IL28B production in IFN-treated peripheral blood mononuclear cells from HCV-infected patients will be determined. Next-generation sequencing of these samples will be used to correlate IL28B genotype to IFN?-induced changes in global gene expression. The functional interplay between these two IFN systems will be assessed in cell culture-based hepatocyte models of HCV infection, followed by next-generation transcriptome profiling. The gene profiling efforts will be used in combination with the candidate's prior ISG screens to pinpoint the strongest and/or most clinically relevant effectors for follow up antiviral mechanism of action studies in the independent phase. This research plan is intended to complement a comprehensive career development plan that includes mentorship in new areas related to deep sequencing technologies and translational research. The mentored phase of this award will be carried out in the laboratory or Dr. Charles Rice at The Rockefeller University, one of the world's leading virology laboratories and a source of significant resources and basic science expertise. As part of the Center for the Study of Hepatitis C, a joint venture with Weill Cornell Medical College and New York Presbyterian Hospital, this environment also offers access to a vibrant clinical and translational research community. Critical to the career development plan are attendance at professional conferences, regular meetings with an advisory committee, and courses that offer instruction in ethics, deep sequencing, and clinical/translational research techniques. Summarily, this training plan should satisfy the candidate's short-term goals of adding new technologies and approaches to an already extensive experimental repertoire, and long term goals of running an independent research program in molecular virology, virus-host cell interactions, and viral pathogenesis.

Public Health Relevance

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with severe pathological sequelae including hepatitis, cirrhosis and hepatocellular carcinoma. HCV is not vaccine preventable and is frequently resistant to available therapies, which are based on interferon. A greater understanding of how interferon acts against HCV may lead to improved treatments for this and other viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK095031-01
Application #
8280675
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2012-04-01
Project End
2012-09-30
Budget Start
2012-04-01
Budget End
2012-09-30
Support Year
1
Fiscal Year
2012
Total Cost
$52,921
Indirect Cost
$3,920
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Schoggins, John W (2014) Interferon-stimulated genes: roles in viral pathogenesis. Curr Opin Virol 6:40-6
Feenstra, Bjarke; Pasternak, Björn; Geller, Frank et al. (2014) Common variants associated with general and MMR vaccine-related febrile seizures. Nat Genet 46:1274-82
Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691-5
Cheon, HyeonJoo; Holvey-Bates, Elise G; Schoggins, John W et al. (2013) IFN*-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J 32:2751-63
Schoggins, John W; Randall, Glenn (2013) Lipids in innate antiviral defense. Cell Host Microbe 14:379-85
Kane, Melissa; Yadav, Shalini S; Bitzegeio, Julia et al. (2013) MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502:563-6