The goal of this project is to characterize the expression profile and signaling pathways of mouse TLRs 1-6. We plan to examine the expression of TLRs 1-6 in various cell types of the immune system, including dendritic cells and their subtypes, macrophages, and T and B lymphocytes and their subtypes. We will look for changes in TLR expression associated with activation of these cell types by various stimuli, such as pro-and anti-inflammatory cytokines. Our main emphasis will be on the analysis of TLR expression in various subpopulations of dendritic cells. We also plan to investigate the signaling pathways activated by different TLRs. We have recently identified several novel gene products involved in mammalian Toll signaling, and we plan to characterize them in detail. We also found differences in the signaling pathways activated by individual members of the Toll family. We plan to further investigate the similarities and differences in the signal transduction pathways activated by the individual TLRs and to analyze in detail the mechanisms that account for these differences. We will investigate where the differences in the signaling pathways lead to the induction of distinct target genes, and how this is related to the expression profile of individual TLRs. Our ultimate goal is to understand whether activation of different TLRs results in the induction of distinct cellular and immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046688-03
Application #
6603093
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Winter, David B
Project Start
2001-09-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$304,110
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ip, W K Eddie; Hoshi, Namiko; Shouval, Dror S et al. (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356:513-519
Okabe, Yasutaka; Medzhitov, Ruslan (2016) Tissue biology perspective on macrophages. Nat Immunol 17:9-17
Okin, Daniel; Medzhitov, Ruslan (2016) The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia. Cell 165:343-56
Wang, Andrew; Huen, Sarah C; Luan, Harding H et al. (2016) Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation. Cell 166:1512-1525.e12
Ip, W K Eddie; Medzhitov, Ruslan (2015) Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun 6:6931
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
Kotas, Maya E; Medzhitov, Ruslan (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816-827
Su, Tian; Bondar, Tanya; Zhou, Xu et al. (2015) Two-signal requirement for growth-promoting function of Yap in hepatocytes. Elife 4:
Bezbradica, Jelena S; Rosenstein, Rachel K; DeMarco, Richard A et al. (2014) A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat Immunol 15:333-42
Colegio, Oscar R; Chu, Ngoc-Quynh; Szabo, Alison L et al. (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559-63

Showing the most recent 10 out of 36 publications