Poorly healing wounds linked to age or diabetes have an annual health care cost of over $25 billion. Current therapies consist of application of recombinant growth factors to stimulate angiogenesis and provisional matrix synthesis, but this approach has had limited effectiveness and is very costly. Thus new approaches to correct both inadequate angiogenesis and the prolonged inflammatory phase of poorly healing wounds are needed. My laboratory has been studying the role of Homeobox (Hox) genes in pathological tissue remodeling and have identified a group of Hox3 genes (HoxA3,B3 and D3) whose expression is upregulated during normal tissue repair but not in compromised diabetic wounds. We developed a topical gene transfer methods to deliver plasmids expressing HoxD3 and HoxA3 and observed significant improvement in healing of diabetic wounds. More recently we observed that that paralogous HoxB3 is the most potent and can improve healing to rates indistinguishable from healthy mice. Our preliminary evidence indicates that along with stimulating angiogenesis, HoxB3 also corrects the prolonged inflammatory phase of poorly healing wounds and promotes influx of immune suppressive late wound macrophages and mast cells. Thus restoring of HoxB3 reprograms poorly healing wounds to allow them to transition from a prolonged inflammatory state to an immunosuppressive state that is conducive to wound resolution. We have also observed changes in a number of other immune cells in diabeetic wounds that are corrected by HoxB3 but the role of these cells has not yet been explored. Thus we propose to conduct studies to identify downstream mediators of HoxB3 and establish the functional roles of changes in immune cell trafficking induced by HoxB3 that contribute to greatly improved wound repair.

Public Health Relevance

Each year up to 6 million individuals are affected by poorly healing wound linked to age or diabetes. As current therapies are not adequte, new approaches to correct both inadequate angiogenesis and the prolonged inflammatory phase of poorly healing wounds are needed. Acute gene therapy with HoxB3 promises a significant improvement over current therapies and would also have relevance to improving stem cell therapy or treating other chornic inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR069495-02
Application #
9316535
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Tseng, Hung H
Project Start
2016-07-15
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$209,220
Indirect Cost
$77,220
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Weaver, Valerie Marie (2017) Cell and tissue mechanics: the new cell biology frontier. Mol Biol Cell 28:1815-1818