Genetic Variation and Immune Responses After Injury
Genetic Variation and Immune Responses After Injury
Our overall hypothesis is that genetic variations in innate immunity genes predispose
 patients to varying responses after injury by altering the systemic and local inflammatory
 responses. In addition, we hypothesize that these genetic differences are associated with
 different clinical outcomes
The goal of this research proposal is to identify relationships that exist between specific
 genetic markers, immune responses to injury and infection (sepsis), and post injury clinical
 outcomes. Specifically, we will investigate the clinical impact of mutations involved in the
 innate immune response, which likely influence host response. To accomplish this goal we will
 collect and analyze data from patients with acute thermal injury, the most quantitative
 inflammatory stimulus experienced by humans. In addition, we propose to further characterize
 the immunologic response parameters to injury and infection, and their role in complicated
 sepsis. In this way, we will identify parameters associated with unfavorable clinical
 outcomes, and determine how these parameters differ among individuals with different
 genotypes. We propose to 1) evaluate associations between candidate SNPs within the NOD2/RIP2
 signaling pathway and clinical outcome following burn injury, 2) evaluate the functional
 effects of alternate alleles at candidate SNPs; finally 3), we will use genetically
 engineered animal models to determine whether mutations in the NOD2 or RIP2 genes alter
 myocardial signal transduction mechanisms shown to play a role in myocardial
 inflammation/dysfunction after burn trauma. These approaches should allow us to evaluate more
 extensively clinically relevant interactions between specific genetic polymorphisms, the
 cellular expression of immune mediators, and burn-induced immune dysfunction. The proposed
 research should uncover genetic and/or acute immune-inflammatory parameters that identify
 patients who are at "high risk" and could as a result make possible the targeted design of
 pharmacologic intervention strategies that will inhibit the toxic effects of LPS and other
 bacterial pathogen components without paralyzing the host immunity of patients
Inclusion Criteria: All burn,trauma, or acute surgery victims admitted to the surgical,
 burn or trauma units within 24 hours of injury will be considered for inclusion.

 Exclusion Criteria:severe immunosuppression, DNR, severe trauma, terminal diseases.

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