Persistent unresolved inflammation impairs diabetic wound healing. The function and fate of wound monocyte/macrophages hold the key to the outcome of wound inflammation. This proposal builds on observations originating from live functional wound macrophages (wm?) and wound fluid (WF) derived from chronic wounds of patients which were then developed further using experimental models. Given current ambiguity in macrophage nomenclature, and proposed misfit of wm? with the M1/M2 nomenclature, for this proposal we classify ?m? based on the pro-inflammatory (m?inf) or pro-resolution/healing (m?heal) functional states. During the last cycle, we reported that i) successful wm? efferocytosis (Eff) helps resolve inflammation; and ii) that efferocytosis was severely impaired (Efflo) in wm? of diabetic wounds causing unresolved inflammation. Recently, our laboratory was the first to report a critical role of miRNA-21 in the regulation of wound inflammation. The proposed study recognizes (i) ?m? efferocytosis functional status, and (ii) ?m? miR- 21 as two critical factors required for advancing pro-inflammatory wm? (m?inf) to m?heal. wm? are attractive therapeutic target for improved wound healing outcomes. Importantly, through nanoparticle based m? targeted delivery of miR-21, and rMFG-E8 application, both factors may be modified with therapeutic intent. Another seminal observation is the detection of FSP1+Collagen1A1 producing fibroblast-like cells (m?F) of myeloid origin at wound-site. This raises the question, do plastic wm? transition to fibroblast-like cells at the wound site? We hypothesize that in the wound microenvironment, efferocytosis and miR-21 are critical determinants of wm? reprograming of m?inf?m?heal or m?inf?m?F functional states. Diabetic wm? suffer from Efflo and miR- 21lo. This combination stalls wm? in m?inf resulting in chronic inflammation. The following 3 aims are thus proposed:
Aim 1 : Test efferocytosis and miR-21 as critical determinants of wound monocyte/macrophage (wm?) fate. 1.1 A subset of wm? undergoes m?inf?m?heal; 1.2 Another unique subset of wm? undergoes m?inf?m?F.
Aim 2 : Determine how diabetes redirects the fate of wm? resulting in derailment of healing. 2.1 Diabetic wm? suffer from two critical impairments, impaired efferocytosis (Efflo) and low miR-21 (miR-21lo), the combination of which stalls wm? in m?inf; 2.2 Targeted nanoparticle delivery of miR-21 to diabetic wm? advances some such cells primarily to m?F; 2.3 In diabetic wm?, correction of miR-21 (2.2) in combination with correction of efferocytosis resumes physiological healing advancing diabetic m?inf?m?heal/m?F.
Aim 3 : Study live wm? and wound-edge tissue biopsies isolated from wounds of diabetic patients testing whether 3.1 wm? transition to m?F; 3.2 correction of miR-21 and efferocytosis advances diabetic wm? to m?inf?m?heal/m?F .

Public Health Relevance

In the United States, skin wounds affect 6.5 million patients placing a major burden, estimated at US $25 billion annually, on society. Persistent inflammation in wound tissue is a major contributor to wound chronicity, specifically in diabetic ulcers. The proposed project aims to identify novel pathways that regulate the function and fate of wound monocyte/macrophages. These cells are major regulators of wound inflammation. Successful completion of the project will offer critical new knowledge that is clinically relevant and aims at improving management of diabetic wound inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK076566-05A1
Application #
9336060
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2008-04-01
Project End
2017-08-31
Budget Start
2016-09-21
Budget End
2017-08-31
Support Year
5
Fiscal Year
2016
Total Cost
$346,500
Indirect Cost
$121,500
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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