Project Details
Description
Project Summary/Abstract
Burn injuries continue to be one of the leading causes of unintentional death and injury in the United States.
Non-fatal burn injuries are a leading cause of morbidity with the most common complications being infectious
related. Thermal injures result in massive fluctuations in the inflammatory and immune responses (e.g., plasma
cytokines, cellular phenotypes, immune function, and soluble proteins) and these changes have been associated
with mortality and infectious complications. However, the underlying mechanisms driving these dysfunctional
responses is still largely unknown both systemically and locally. Our primary goal is to investigate the systemic
and localized mechanisms of immune dysfunction following pediatric thermal injury to provide useful biomarkers
to identify those at highest risk to develop subsequent infection with a goal to develop therapies to improve
patient outcomes. Over the next five years we will pursue three integrated research plans that use both pediatric
blood and tissue samples as well as an established juvenile murine model of burn injury and infection, to
investigate the mechanisms of immune dysfunction after burn injury. Research Plan 1 will investigate the
mechanisms underlying lymphocyte dysfunction after severe burn injury. In this work we will assess the cell
surface expression of lymphocyte co-inhibitory molecules, examine apoptotic markers on isolated lymphocytes,
and perform functional assays. This work will provide insight into the mechanisms surrounding lymphocyte
dysfunction and guide future immunomodulatory therapies that can target these specific mechanisms. Research
Plan 2 will evaluate the differentiation of systemic monocytes to tissue macrophages after severe burn injury and
post-burn complications. In this work we will perform functional assays on isolated systemic monocyte
populations and isolated tissue macrophages. This work will lead us to a more complete mechanistic
understanding of the differentiation of systemic monocyte populations to the localized macrophages in the wound
bed. This information will inform the best route of administration (systemic or topical) to apply immunomodulatory
therapy to augment these macrophages and improve tissue level outcomes. Research Plan 3 will elucidate the
potential benefits of FDA-approved immunomodulator therapies after severe burn injury to prevent post-burn
complications. This work will use combination therapies, ex vivo in pediatric samples and in vivo in our murine
burn model, to assess changes in immune function. The findings from this study will be important to advance the
design of future immunostimulatory clinical trials in this population as well as other forms of surgical
predisposition to sepsis such as trauma and major surgery. Moreover, this could serve as a model for other age
groups of burn injuries. Together, these projects will provide an important building block for developing
appropriate therapeutics in treating burn wounds that can simultaneously help control inflammation, prevent
infection, and assist in wound healing, which is an absolute necessity for burn care research.
Status | Active |
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Effective start/end date | 09/1/23 → 06/30/24 |
Funding
- National Institute of General Medical Sciences: $390,000.00
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