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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI056234-09A1
Application #
8238589
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Davidson, Wendy F
Project Start
2003-09-01
Project End
2016-10-31
Budget Start
2011-11-09
Budget End
2012-10-31
Support Year
9
Fiscal Year
2012
Total Cost
$412,500
Indirect Cost
$162,500
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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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
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