A central scientific question of this competing proposal's renewal is finding novel functions of immunologically relevant genes by means of classical genetic analysis in genetically diverse wild-derived mice. We have shown and continue to show that, with respect to regulation of immune responses, wild-derived mice resemble human phenotype better than classical laboratory mice. One line of inquiry continues investigation of TIRAP-dependent activation of IRAK2 followed by specific recruitment of the p38 MAP kinase, which is hyperactivated in wild- derived but not laboratory mice. We have proposed a model of MyD88-independent recruitment of IRAK2 and TIRAP in wild-derived mice, which leads to a specific activation of p38. If confirmed, this model will challenge several well-established paradigms such as simultaneous activation of MAP kinases via TLRs and MyD88- dependent activation of p38 thus broadening existing models of TLR-mediated activation and providing additional mechanistic insight. Another phenotype that we propose to investigate in wild-derived mice is their remarkable resistance to TNF-induced lethality, which is, according to our preliminary data, a genetic trait that is conferred by four loci, which we propose to identify. Given our expertise and track record in mapping and positional cloning, it is likely that we will find novel components of TNF-receptor pathway, which protect mice and presumably humans from TNF-induced lethality. To explain the trait, we generated our central hypothesis in that TNF-resistance in MSM mice is biased towards pro-survival as compared to cytotoxic signaling that leads to necrosis, and we provide feasible scientific plan to prove that. Thus, the scientific impact of this proposal is high because it will identify component, which are capable of defining the outcome of TNF-activation. In addition, the proposed genetic analysis will help identifying genes that otherwise would be difficult to predict in the absence of """""""" strong educated guess"""""""". Most importantly, the identification of these genes will be of high relevance to human health given several hundred thousand of patients suffering each year from septic shock. In addition to cloning of the TNF-resistance, which is clearly a priority of this proposal, we provide a research plan aimed at revealing in vivo functions of two genes that we identified in the previous cycle. ) )

Public Health Relevance

Mechanisms of control of septic shock and human responses to G(-) infections and lipopolysaccharide (LPS), are poorly understood. The proposal is concerned with identification of genes that confer resistance to LPS and its main effector TNF (tumor necrosis factor). The identification of these genes could lead to diagnostics or even open new opportunities for therapeutic intervention. Importantly, targeting the TNF-activation pathway, a relatively late event in the progression of septic shock, will likely be more beneficial than therapies currently explored by several pharmaceutical companies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Davidson, Wendy F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
Schools of Medicine
United States
Zip Code
Ram, Daniel R; Ilyukha, Vladimir; Volkova, Tatyana et al. (2016) Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo. Proc Natl Acad Sci U S A 113:1606-11
Surpris, Guy; Chan, Jennie; Thompson, Mikayla et al. (2016) Cutting Edge: Novel Tmem173 Allele Reveals Importance of STING N Terminus in Trafficking and Type I IFN Production. J Immunol 196:547-52
Surpris, Guy; Poltorak, Alexander (2016) The expanding regulatory network of STING-mediated signaling. Curr Opin Microbiol 32:144-50
Schworer, Stephen A; Smirnova, Irina I; Kurbatova, Irina et al. (2014) Toll-like receptor-mediated down-regulation of the deubiquitinase cylindromatosis (CYLD) protects macrophages from necroptosis in wild-derived mice. J Biol Chem 289:14422-33
Moseman, Annie Park; Moseman, E Ashley; Schworer, Stephen et al. (2013) Mannose receptor 1 mediates cellular uptake and endosomal delivery of CpG-motif containing oligodeoxynucleotides. J Immunol 191:5615-24
Smith, Patrick M; Jacque, Berri; Conner, James R et al. (2011) IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection. PLoS Pathog 7:e1002272
Conner, James R; Smirnova, Irina I; Moseman, Annie Park et al. (2010) IRAK1BP1 inhibits inflammation by promoting nuclear translocation of NF-kappaB p50. Proc Natl Acad Sci U S A 107:11477-82
Conner, James R; Smirnova, Irina I; Poltorak, Alexander (2009) A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. J Exp Med 206:1615-31
Juris, Stephen J; Melnyk, Roman A; Bolcome 3rd, Robert E et al. (2007) Cross-linked forms of the isolated N-terminal domain of the lethal factor are potent inhibitors of anthrax toxin. Infect Immun 75:5052-8
Jacque, Berri; Stephan, Kristin; Smirnova, Irina et al. (2006) Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS-induced lethality. Eur J Immunol 36:3007-16

Showing the most recent 10 out of 11 publications