In the United States, recent estimates suggest that more than 750,000 patients per year are at high risk for developing septic shock with mortality rates reaching 60%. Thus there are huge societal and financial costs associated with this syndrome. Because of its high incidence and poor prognosis, we propose basic research focused on the innate immune system and its interface with the adaptive immune system. We acknowledge that the pathophysiology of severe sepsis/shock is exceedingly complex. There is little doubt, however, that there is often a progression from infection --) normal systemic response (sepsis) --) severe sepsis --) shock and that the primary event in this sequence is infection. There is also important evidence that the intensity of the inflammatory process at the site(s) of infection determine the severity of the systemic reaction to infection, and thus the occurrence of severe sepsis and shock. It is our contention that the only means to approach such a complex system is to use appropriate cellular and animal model systems and apply the principles of systems biology in their analysis. To accomplish this we have brought together investigators with many different scientific backgrounds and specialties that include cutting-edge bioinformatics, genomic and proteomic analyses, cell biology, studies of innate and adaptive immunity, biological network modeling etc. Most importantly, we have combined experts in the field of innate immunity with """"""""new scientific blood"""""""" such as experts in the fields of genomics, proteomics and bioinformatics. It is our contention that in the context of this GLUE GRANT this combination of investigators will, in our highly interactive and interdependent setting, substantially expand the formulation of new concepts for this field. This effort will form the basis for a great many hypothesis-driven studies by the scientific community at-large, both basic and clinical. These studies will also identify potential new drug targets that could lead to new therapies for sepsis and shock. This would directly impact the clinical outcome of these critically ill patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TB-2 (GG))
Program Officer
Chiodetti, Lynda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Tabeta, Koichi; Du, Xin; Arimatsu, Kei et al. (2017) An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. Sci Rep 7:11717
Siggs, Owen M; Miosge, Lisa A; Daley, Stephen R et al. (2015) Quantitative reduction of the TCR adapter protein SLP-76 unbalances immunity and immune regulation. J Immunol 194:2587-95
Siggs, Owen M; Yates, Adèle L; Schlenner, Susan et al. (2014) A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction. Immunology 141:587-95
Wang, James Q; Jeelall, Yogesh S; Beutler, Bruce et al. (2014) Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance. J Exp Med 211:413-26
Cho, Vicky; Mei, Yan; Sanny, Arleen et al. (2014) The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA. Genome Biol 15:R26
Altin, John A; Daley, Stephen R; Howitt, Jason et al. (2014) Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells. Proc Natl Acad Sci U S A 111:2067-74
Crawford, Greg; Enders, Anselm; Gileadi, Uzi et al. (2013) DOCK8 is critical for the survival and function of NKT cells. Blood 122:2052-61
Teh, C E; Horikawa, K; Arnold, C N et al. (2013) Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation. Genes Immun 14:223-33
Andrews, T D; Sjollema, G; Goodnow, C C (2013) Understanding the immunological impact of the human mutation explosion. Trends Immunol 34:99-106
Enders, Anselm; Stankovic, Sanda; Teh, Charis et al. (2012) ZBTB7B (Th-POK) regulates the development of IL-17-producing CD1d-restricted mouse NKT cells. J Immunol 189:5240-9

Showing the most recent 10 out of 46 publications