. Dr. Ko is enrolled in a uniquely combined periodontics and Doctor of Science in Dentistry (DScD) program at the University of Pennsylvania School of Dental Medicine. Under the mentorship of Dr. Dana Graves and the thesis committee, Dr. Ko will investigate the effect of diabetes on mesenchymal stem cells (MSCs) during hard and soft tissue wound healing. This topic of interest is important in the field of periodontology as wound healing of the hard and soft tissue is a critical component of numerous periodontal diseases that are often exacerbated by diabetes. Dr. Ko is committed to a career in academics, which will be greatly enhanced by the educational, technical and career development trainings afforded by the K08 Award. The established specialty/DScD program at Penn will serve as an important step stone for Dr. Ko's long term goal to eventually emerge as an independent researcher, studying how systemic disease alters local stem cell behavior in the oral cavity. Diabetes delays hard and soft tissue wound healing through persistent inflammation. How diabetes leads to greater inflammation in the healing environment remains largely unknown. Recent advances in transplantation studies have demonstrated that MSCs play an essential anti-inflammatory role. Diabetes may interfere with their anti-inflammatory function to enhance the inflammatory environment. Prolonged activation of nuclear-factor kappa B (NF-?B), a master inflammatory transcription factor, has been implicated in diabetic complications. We propose that NF-?B is activated by the diabetic conditions in MSCs and contributes to impaired diabetic soft and hard tissue wound healing. To address this issue, we generated mice that have lineage specific deletion of IKK-beta in MSCs, a kinase essential for activation of NF-?B. Our preliminary data demonstrate that conditional deletion of IKK-beta in MSCs increases the number of MSCs, reduces the level of inflammation and improves the outcome in fracture healing in diabetic animals, suggesting a negative role of NF-?B in these cells in diabetic healing. Thus, we propose a central hypothesis that activation of NF-?B in MSCs in diabetic conditions negatively affects hard and soft tissue healing by reducing the number of MSCs and by interfering with the anti-inflammatory function of MSCs.
Aim 1 will establish the important role of intrinsic NF-?B in regulating MSC number and function during fracture and gingival wound healing under diabetic condition.
Aim 2 will investigate whether diabetes alters regulation of genes associated with delayed healing, and determine if this is reversed by inhibiting NF-?B activation in MSCs.
Aim 3 will determine whether NF-?B inhibitor is a novel treatment for diabetic fracture and gingival wound healing by improving MSC activities. Collectively, these studies will further our understanding of mechanism underlying diabetic complications in hard and soft tissue wound healing. Successful completion of this proposal may further offer an alternative therapeutic approach to consider in the treatment of non-healing diabetic wounds by targeting endogenous MSCs with specific NF-?B inhibitors.

Public Health Relevance

/public health relevance. The project proposed here will investigate how diabetes affects mesenchymal stem cells that are important for hard and soft tissue healing. We will test if diabetes activates an inflammatory protein, NF-kB, and mediates the negative effects in these stem cells. Our studies may provide a novel therapeutic approach to target this protein to improve the function of the stem cells in the treatment of non-healing diabetic wounds.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Clinical Investigator Award (CIA) (K08)
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NIDR Special Grants Review Committee (DSR)
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King, Lynn M
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University of Pennsylvania
Schools of Dentistry/Oral Hygn
United States
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