My laboratory recently uncovered an unexpected and intriguing role for mature adipocytes during skin wound healing: control of inflammation after injury. In particular, we identified that mature adipocytes undergo lipolysis to release of lipids into wound beds to initiate inflammation. Our findings are important for several reasons. First, adipocytes have been shown to improve wound healing and scarring yet how mature adipocytes function in this process is unclear. Second, the release of lipids from adipocytes, or lipolysis, has been shown to modulate inflammation in traditional depots, yet whether skin adipocytes regulate the essential inflammatory processes following skin injury is not known. Furthermore, adipocytes and their derivatives (fatty acids and/or cytokines) are a tractable cell type to create a personalized therapy to promote healing in patients with chronic wounds. Finally, glucocorticoids are known to influence adipocyte biology and also to inhibit wound healing, but whether the effect of glucocorticoids on wound healing is mediated through adipocytes is not known. Through three focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of adipocytes, adipocyte lipolysis, lipidomics, lipid tracking, bioengineered tissue models, and a novel bioanalytical assay platform to define the function adipocyte-derived lipids during skin injury and how these are altered with glucocorticoids, age, diabetes and obesity. We will (1) identify the role of adipocyte derived lipids during inflammation during skin wound healing, (2) determine whether glucocorticoids influence wound healing through depletion of lipids from mature, dermal adipocytes, (3) define whether adipocyte fatty acids can modulate wound healing in aged and diabetic mice or are altered in human skin. These studies will identify specific pro-healing cell populations and molecules that can be utilized to promote healing in human patients with defective wound healing or other skin disorders.

Public Health Relevance

A thorough understanding of cells and molecules that regulate tissue repair and fibrosis is essential for the generation of tissue-specific regenerative therapies to effectively treat human disease. Since the manner in which adipocytes function during skin wound healing is largely unknown, we will define how these major but poorly understood cells function during skin wound healing. Our work will improve our understanding of the cells and molecules that control basic skin regeneration, how adipocytes function in this process, and will have global relevance for other tissues that contain adipocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR075412-02
Application #
9898323
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Belkin, Alexey
Project Start
2019-04-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520