Chronic wounds associated with diabetes are a burgeoning health problem in the United States. A common characteristic of these poorly healing wounds is a persistent inflammatory response, with accumulation of pro-inflammatory macrophages. The central hypothesis of this proposal is that diabetes induces overproduction of pro-inflammatory monocytes and reduces levels of pro-healing monocytes that each contribute to the poor healing responses in diabetic wounds. We propose a translational study involving both mouse models and human patients with three Specific Aims: in the first Aim, we will determine whether sustained activity of the NLRP3 inflammasome/IL-1? pathway results in overproduction of pro-inflammatory monocytes and impaired healing in diabetes. In the second Aim, we will determine whether impaired activity of Nur77 reduces levels of pro-healing monocytes contributing to impaired healing in diabetes. In the third Aim, we will perform an informative pilot double-blinded, randomized clinical trial to determine whether topical treatment with glyburide can modulate monocyte subsets prior to and/or after wound infiltration and improve healing in diabetes. The proposed experiments will improve knowledge of the role of monocyte subsets during impaired healing in diabetic mice and humans along with cell-intrinsic and cell-extrinsic mechanisms that regulate production of these cells. The impact of these studies lies in the initial translation to a therapy that targets monocyte subsets in diabetic patients to induce resolution of inflammation and stimulate healing responses in hard-to-heal wounds. In addition, the studies could lead to development of assays that involve monitoring blood monocyte subsets as cellular biomarkers to aid in the selection of treatment options for diabetic patients with chronic wounds.

Public Health Relevance

Chronic wounds associated with diabetes represent a burgeoning health problem in the United States with millions of patients suffering from these wounds and the associated treatment costing billions of dollars per year. In the proposed research, we will investigate whether diabetes induces overproduction of pro-inflammatory monocytes and reduces levels of pro- healing monocytes that each contribute to the poor healing responses in diabetic wounds. Importantly, we will translate our basic science findings into a clinical trial designed to determine whether topical treatment of wounds with glyburide, a common anti-diabetic medication, can reduce inflammation and improve wound healing. The long-term goal of this project is to reduce the socioeconomic burden of chronic diabetic wounds and improve the quality of life of diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092850-08
Application #
9632827
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Garcia, Martha
Project Start
2011-09-30
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2021-01-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Nutrition
Type
Sch Allied Health Professions
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Fang, Milie M; Barman, Pijus K; Thiruppathi, Muthusamy et al. (2018) Oxidant Signaling Mediated by Nox2 in Neutrophils Promotes Regenerative Myelopoiesis and Tissue Recovery following Ischemic Damage. J Immunol 201:2414-2426
Spiller, Kara L; Koh, Timothy J (2017) Macrophage-based therapeutic strategies in regenerative medicine. Adv Drug Deliv Rev 122:74-83
Chokpaisarn, Julalak; Urao, Norifumi; Voravuthikunchai, Supayang P et al. (2017) Quercus infectoria inhibits Set7/NF-?B inflammatory pathway in macrophages exposed to a diabetic environment. Cytokine 94:29-36
Urao, Norifumi; Okonkwo, Uzoagu A; Fang, Milie M et al. (2016) MicroCT angiography detects vascular formation and regression in skin wound healing. Microvasc Res 106:57-66
Salazar, Jay J; Ennis, William J; Koh, Timothy J (2016) Diabetes medications: Impact on inflammation and wound healing. J Diabetes Complications 30:746-52
Weinheimer-Haus, Eileen M; Mirza, Rita E; Koh, Timothy J (2015) Nod-like receptor protein-3 inflammasome plays an important role during early stages of wound healing. PLoS One 10:e0119106
Mirza, Rita E; Fang, Milie M; Novak, Margaret L et al. (2015) Macrophage PPAR? and impaired wound healing in type 2 diabetes. J Pathol 236:433-44
Mirza, Rita E; Koh, Timothy J (2015) Contributions of cell subsets to cytokine production during normal and impaired wound healing. Cytokine 71:409-12
Rayahin, Jamie E; Buhrman, Jason S; Zhang, Yu et al. (2015) High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng 1:481-493
Chen, Lin; Mirza, Rita; Kwon, Young et al. (2015) The murine excisional wound model: Contraction revisited. Wound Repair Regen 23:874-7

Showing the most recent 10 out of 16 publications