The overarching goal of this clinical-translational study is to advance nursing science and the wound care field, by elucidating critical molecular pathways driving recalcitrant wounds, and correlating them with patient-centric outcome measures including pain and wound outcomes. Utilizing the resources of the Georgetown-Howard Center for Clinical and Translational Science and the J. Craig Venter Institute, the investigators will draw upon a multidisciplinary team to apply high-throughput genomic technologies and investigate the interplay between host immune and angiogenesis pathways, wound biofilm, patient reported pain and analgesic use in chronic wounds. To achieve these goals we specifically aim: 1.Toestablish host molecular signatures predictive of wound outcome. In a well phenotyped cohort of patients with healing and recalcitrant chronic wounds, we predict there will be differential expression of immune, eicosanoid signaling and angiogenic pathways. We will investigate this by: a. Identifying differentially expressed genes based on mRNA expression profiles between recalcitrant and healing chronic wounds. b. Validating mRNA expression profiles using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. 2. To establish the bacterial profile, virulence and pathogenicity markers and correlate them with host immune response pathways and wound outcome. We predict that recalcitrant chronic wounds will exhibit different wound-bed bacterial profiles, virulence or pathogenicity markers, and that these profiles will correlate with host immune response signatures and pain. To investigate this hypothesis we will: a. Use bacterial 16S ribosomal RNA gene profiles to compare wound biofilm bacterial diversity between healing and recalcitrant chronic wounds. b. Correlate the microbiome profile with host immune response, pain, co-morbidities and outcome. 3. To correlate wound-related pain with pathways of eicosanoid signalling, cumulative analgesic requirements and wound outcome. We postulate that recalcitrant wounds will exhibit up regulation of eicosanoid signalling pathways and that this will correlate with wound-related pain scores, analgesic use and outcome. We propose: a. Correlating patient-reported pain scores with eicosanoid signalling pathways. b. Investigating possible relationships between exposure to different classes of analgesics, cumulative analgesic doses and wound outcome.

Public Health Relevance

Chronic wounds are major public health problem affecting 1% of the US population and costing approximately $25 billion per year. Recent studies suggest that mortality in patients with chronic wounds approaches that seen in some malignancies, and there is an urgent need to identify effective therapies that both improve ultimate wound outcome, and alleviate patient symptoms and suffering. The proposed research will focus on both of these aims, by elucidating critical molecular pathways driving recalcitrant wounds, facilitating translation of these findings to identify clinically predictive biomarkers, and identiying therapeutic targets to improve outcomes and wound related pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
7R01NR013888-03
Application #
8879429
Study Section
Special Emphasis Panel (ZNR1-REV-T (11))
Program Officer
Tully, Lois
Project Start
2014-08-08
Project End
2017-05-31
Budget Start
2014-08-08
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$390,349
Indirect Cost
$121,700
Name
George Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Shanmugam, Victoria K; McNish, Sean; Duncan, Joanna et al. (2015) Late failure of a split-thickness skin graft in the setting of homozygous factor V Leiden mutation: a case report and correlative animal model from the Wound Etiology and Healing (WE-HEAL) study. Int Wound J 12:537-44
Chen, Ya-Wen; Wang, Jehng-Kang; Chou, Fen-Pai et al. (2014) Matriptase regulates proliferation and early, but not terminal, differentiation of human keratinocytes. J Invest Dermatol 134:405-14
Shanmugam, Victoria K; McNish, Sean; Shara, Nawar et al. (2013) Chronic leg ulceration associated with polycythemia vera responding to ruxolitinib (Jakafi(ýý)). J Foot Ankle Surg 52:781-5
Frech, Tracy M; Shanmugam, Victoria K; Shah, Ami A et al. (2013) Treatment of early diffuse systemic sclerosis skin disease. Clin Exp Rheumatol 31:166-71