The ability to heal oral wounds is an important aspect of an individual's health and is negatively affected by diabetes. Surprisingly little is known about the impact of diabetes on the molecular events of oral wound healing. Our recently published studies demonstrate that activation of the transcription factor forkhead box O1 (Foxo1) in keratinocytes plays important but surprisingly, opposite roles in re-epithelialization of wounds in diabetic and normoglycemic animals. Preliminary Data shows that keratinocytes promote connective tissue healing under normal conditions through a FOXO1 dependent mechanism but inhibit connective tissue formation in diabetic wounds. The goal of this proposal is to unravel the molecular mechanisms through which FOXO1 differentially activates keratinocytes to promote or inhibit connective tissue healing depending upon normoglycemic or diabetic conditions. The results will establish how FOXO1 may be an important therapeutic target in promoting wound healing in diabetes.
Aim 1 will establish mechanisms through which two key FOXO1 downstream targets (TGF?1 and MMP9) are inversely modulated by diabetic conditions in vitro (high glucose and advanced glycation end products) in gingival keratinocytes and compare the results with epidermal keratinocytes.
Aim 2 will establish mechanisms through which keratinocytes enhance connective tissue healing in a FOXO1 dependent manner in normoglycemic wounds but inhibit it in diabetic wounds. These studies will focus on the impact of FOXO1 in organizing the expression of factors by keratinocytes that stimulate fibroblasts and endothelial cells in normal conditions but fail to do this in diabetic conditions. The goal of Aim 3 is to carry out translational studies and establish functional to rescue diabetic healing. They will determine whether modulation of FOXO1 downstream targets reverses diabetes impaired gingival and dermal healing and whether FOXO1 is a good therapeutic target to improve diabetic healing. The proposed studies are strongly supported by Preliminary Data, will definitively test whether FOXO1 plays a central role in impaired diabetic oral wound healing and will provide the basis for future studies by establishing whether its inhibition has therapeutic value.

Public Health Relevance

The goal of this proposal is to unravel the molecular mechanisms through which the transcription factor FOXO1 differentially activates keratinocytes to promote connective tissue healing in normal oral wounds or inhibit it in diabetic wounds. The proposed studies are strongly supported by Preliminary Data, will definitively test whether FOXO1 plays a central role in impaired diabetic oral wound healing and will provide the basis for future studies by establishing whether FOXO1 inhibition has therapeutic value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019108-10
Application #
9987307
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
2009-09-25
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Jeon, Hyeran Helen; Yu, Quan; Lu, Yongjian et al. (2018) FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds. J Pathol 245:258-264
Song, L; Dong, G; Guo, L et al. (2018) The function of dendritic cells in modulating the host response. Mol Oral Microbiol 33:13-21
Zhang, Chenying; Lim, Jason; Liu, Jian et al. (2017) FOXO1 expression in keratinocytes promotes connective tissue healing. Sci Rep 7:42834
Dong, Guangyu; Song, Liang; Tian, Chen et al. (2017) FOXO1 Regulates Bacteria-Induced Neutrophil Activity. Front Immunol 8:1088
Zhang, Chenying; Lim, Jason; Jeon, Hyeran Helen et al. (2017) FOXO1 deletion in keratinocytes improves diabetic wound healing through MMP9 regulation. Sci Rep 7:10565
Lim, Jason C; Ko, Kang I; Mattos, Marcelo et al. (2017) TNF? contributes to diabetes impaired angiogenesis in fracture healing. Bone 99:26-38
Wang, Yu; Dong, Guangyu; Jeon, Hyeran Helen et al. (2015) FOXO1 mediates RANKL-induced osteoclast formation and activity. J Immunol 194:2878-87
Xiao, E; Graves, D T (2015) Impact of Diabetes on the Protective Role of FOXO1 in Wound Healing. J Dent Res 94:1025-6
Xu, Fanxing; Othman, Badr; Lim, Jason et al. (2015) Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds. Diabetes 64:243-56
Coimbra, L S; Steffens, J P; Alsadun, S et al. (2015) Clopidogrel Enhances Mesenchymal Stem Cell Proliferation Following Periodontitis. J Dent Res 94:1691-7

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