The Type I human interferons, interferon-alpha, beta and -omega (12 Hu-IFN-alpha species, Hu-IFN-beta and Hu-IFN-omega), were among the first cytokines purified, cloned and introduced into the clinical arena. Of these interferons, Hu-IFN-alpha and Hu-IFN-beta are used world wide for treating cancers, viral diseases, multiple sclerosis and other diseases. The efforts of this application flow from work on interferons over the past two decades in the PI's laboratory.
The aims of this proposal are to understand the mechanisms by which the various human Type I interferon species produce different biological responses despite the fact that they interact with the same receptor. The overall hypothesis to be tested is that the individual Type I interferons interact with the receptor quite distinctly producing unique patterns of signal transduction that result in the qualitative/quantitative activation or repression of different genes. To achieve the aims the power of DNA microarray technology will be used to identify the genes induced or repressed by the various Type I interferons. These genes will then provide leads to unravel the underlying mechanisms by which these interferons function.
The specific aims are: determine the specific genes induced or respressed by each of the Type I interferons with the use of DNA microarrays; analyze the promoters of the genes induced or repressed by the individual Type I interferons to discover new pathways by which they function; determine the qualitative and quantitative differences in signal transduction by the Type I interferons to learn how these differences contribute to differences in activities of the interferons; and assess the role of the Type I interferons in post-transcriptional control of gene expression. This application represents a comprehensive approach to understand the activities and mechanism of action of the Type I interferon family of cytokines. Particular attention is focused on defining the pathways by which each member of the family exhibits unique activities while acting via the same receptor complex. Identification of all the pathways initiated through the Type I interferon receptor will provide an opportunity to develop new interferons and new approaches to treat many diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI036450-08S1
Application #
6786552
Study Section
Virology Study Section (VR)
Program Officer
Nasseri, M Faraz
Project Start
1995-09-30
Project End
2005-02-28
Budget Start
2003-08-15
Budget End
2004-02-29
Support Year
8
Fiscal Year
2003
Total Cost
$38,891
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Genetics
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Krause, Christopher D; Izotova, Lara S; Pestka, Sidney (2013) Analytical use of multi-protein Fluorescence Resonance Energy Transfer to demonstrate membrane-facilitated interactions within cytokine receptor complexes. Cytokine 64:298-309
Krause, Christopher D; Digioia, Gina; Izotova, Lara S et al. (2013) Improving the spectral analysis of Fluorescence Resonance Energy Transfer in live cells: application to interferon receptors and Janus kinases. Cytokine 64:272-85
Krause, Christopher D; Digioia, Gina; Izotova, Lara S et al. (2013) Ligand-independent interaction of the type I interferon receptor complex is necessary to observe its biological activity. Cytokine 64:286-97
Walberg, Kristin; Baron, Samuel; Poast, Joyce et al. (2008) Interferon protects mice against inhalation anthrax. J Interferon Cytokine Res 28:597-601
Krause, Christopher D; Pestka, Sidney (2007) Historical developments in the research of interferon receptors. Cytokine Growth Factor Rev 18:473-82
Qu, Yongxia; Adler, Victor; Izotova, Lara et al. (2007) The dual-specificity kinases, TOPK and DYRK1A, are critical for oocyte maturation induced by wild-type--but not by oncogenic--ras-p21 protein. Front Biosci 12:5089-97
Krause, Christopher D; Yang, Zhi-Hong; Kim, Young-Sun et al. (2007) Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol Ther 113:50-87
Pestka, Sidney (2007) The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 282:20047-51
Krause, Christopher D; Mei, Erwen; Mirochnitchenko, Olga et al. (2006) Interactions among the components of the interleukin-10 receptor complex. Biochem Biophys Res Commun 340:377-85
Qu, Yongxia; Adler, Victor; Chu, Tearina et al. (2006) Two dual specificity kinases are preferentially induced by wild-type rather than by oncogenic RAS-P21 in Xenopus oocytes. Front Biosci 11:2420-7

Showing the most recent 10 out of 60 publications