Despite significant advances in the treatment of Type 2 diabetes (T2D) and peripheral vascular disease, wound healing rates have not changed over the past 30 years, with 80,000 amputations performed annually for non-healing diabetic wounds with an associated 3-year mortality rate of 20-50%. In diabetic wounds, a chronic inflammatory state is maintained by imbalances between pro and anti-inflammatory cytokines produced by immune cells, namely macrophages. The persistent pro-inflammatory, M1 macrophage phenotype in the wound effectively prevents healing. Since these peripheral immune cells are mostly derived from bone marrow (BM) hematopoietic progenitor cells and recent evidence suggests that epigenetics plays a key role in influencing immune cell phenotypes, we hypothesize that changes in the BM progenitor cells result in altered peripheral phenotypes. To this end, the candidate (Dr. Katherine Gallagher) seeks to examine the role of epigenetic changes at the BM level on peripheral macrophage phenotypes and the subsequent influence on diabetic wound healing. The overall goal of this application is to support the candidate's continued training and development as an independent investigator in immunology-based, wound healing research. The career development plan is based on coursework, guidance from mentors, and the practical application of skills through research. The candidate's main research goals are to determine whether epigenetic changes occur in BM progenitor cells that result in a "programmed and persistent" peripheral macrophage phenotype, which negatively impacts wound healing in T2D. The major themes of the candidate's research interests are reflected in the Specific Aims of this proposal: (1) to identify epigenetic changes in BM progenitor cells and determine their influence on M1 macrophage phenotypes in diabetic wound healing (2) to determine the role of adipose tissue nutrient/cytokine-directed chromatin modifications in T2D BM-derived progenitor cells, and (3) to examine the influence of histone methylation in human T2D BM-derived hematopoietic stem cells (HSC) on the M1 phenotype. Successful completion of these studies should increase our understanding of the pathologic role of epigenetic changes on T2D BM-derived progenitor cells and their effect on peripheral macrophages and wound healing.

Public Health Relevance

In patients with chronic non-healing diabetic wounds, current therapies are ineffective and limb loss is often the result. The proposed work will (1) examine the role of epigenetic changes at the bone marrow level on diabetic peripheral macrophages, (2) determine how nutrients/cytokines influence epigenetic changes in the diabetic bone marrow, and (3) examine human diabetic bone marrow hematopoietic stem cells and peripheral macrophages for epigenetic changes resulting in an M1 macrophage phenotype. Knowledge gained from our studies could lead to new targeted therapy for diabetic wounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK102357-02
Application #
8731893
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M2))
Program Officer
Hyde, James F
Project Start
2013-09-09
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$154,904
Indirect Cost
$11,104
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109