Genetic Variation and Immune Responses After Injury
| Status: | Completed |
|---|---|
| Conditions: | Pneumonia, Hospital |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/2/2016 |
| Start Date: | August 2003 |
| End Date: | October 2011 |
| Contact: | Fernando A Rivera-Chavez, MD |
| Email: | fernando.rivera@utsouthwestern.edu |
| Phone: | 214-648-3534 |
Genetics of Innate Immune Response After Burn Trauma
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
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
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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