The focus of my graduate research is to investigate and elucidate the roles of matrix metalloproteinases (MMPs) in wound healing. The complexities of MMP involvement in human diseases originate from many levels, including but not limited to, the inability to differentiate diverse forms of MMPs, the lack of methods to identify the active MMPs during progression of diseases, and the lack of selective MMP inhibitors. However, using the novel inhibitor-tethered resin technology from our lab, I was able to identify active MMP-8 and MMP-9 that are involved in human chronic wounds, just like we have accomplished in our mouse model. Profiling MMPs from chronic wounds will open the doors for pharmacological intervention in this disease for which therapeutic options are limited. I have a strong interest in learning how to translate basic science findings from the laboratory to the clinic. Working in the multidisciplinary labs of Profs. Shahriar Mobashery and Mayland Chang, I have the unique opportunity to gain invaluable training from the two experienced mentors. Prof. Mobashery is a renowned leader in the mechanisms of antibacterial drug resistance and Prof. Chang provides the expertise and experience of 28 years working in preclinical and clinical drug development, including bioanalytical chemistry. My hands-on training has expanded from biochemistry to microbiology, pharmacology, and analytical chemistry to advance my research project. I have shown that topical application of MMP-8 and MMP-13 accelerates chronic wound healing. I also demonstrated the synergic effect of MMP-9 inhibition and MMP-8 application in combination therapy that further promotes wound healing, which was published in P.N.A.S. My research becomes more clinically relevant because I confirmed that active MMP-8 and MMP-9 exist in patient chronic wounds. These results validate our mouse model in studying the mechanisms of pathology and repair of human chronic wounds. I have presented my research at both campus-wide symposiums and national conferences. Being a part of CBBI Program will enable me to gain multi-disciplinary training to further investigate the roles of MMP-8 and MMP-9 in wound healing in both mice and humans. The interdisciplinary experience and knowledge from my graduate research will prepare me for a successful independent career in discovery and development of pharmaceutical therapies.
The Beneficial and Detrimental Roles of Matrix Metalloproteinases
in Diabetic Wound Repair
Department of Chemistry and Biochemistry, Freimann Life Science Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556
Chronic wounds affect 6.5 million individuals in the United States, with the medical cost reaching $18.3 billion annually. The elevated glucose in diabetic patients leads to many complications, including impaired wound healing, which results in 73,000 annual amputations in the United States. Fifty percent of patients die within 5 years after amputations. In addition, acute wounds occur in patients after surgery or burns. Approximately 40 million inpatient and 31.5 million outpatient surgeries are performed in the United States every year. It has been recognized that matrix metalloproteinases (MMPs) play important roles in wound healing, since they are involved in the turnover and remodeling of the extracellular matrix. Previously, we identified active MMP-8 in both diabetic and non-diabetic wounds, whereas active MMP-9 was upregulated in only diabetic wounds and demonstrated that MMP-9 plays a detrimental role, while MMP-8 is beneficial for wound healing by the use of selective inhibitors. Here, we demonstrate that topical treatment with the collagenase MMP-8 accelerates wound healing and increases re-epithelialization in both diabetic and non-diabetic animals. Exogenous application of MMP-8 reduces inflammatory cytokines and promotes angiogenesis in the mouse wound model. Exogenous application of collagenase MMP-13―a closely related enzyme to MMP-8―also promotes wound repair in diabetic and non-diabetic mice. Topical treatment with a novel highly selective inhibitor of MMP-9 (compound ND-336) or ablation of MMP-9 accelerates diabetic wound healing by lowering inflammation, and enhancing angiogenesis in the wounds. Furthermore, the combined topical application of ND-336 and active MMP-8 enhance the healing even more, in a strategy that holds considerable promise in healing of diabetic wounds. Concurrently, we identified active MMP-8 and MMP-9 in wounds of patients with diabetic foot ulcers, indicating that mechanism of pathology and repair are similar in diabetic mice and diabetic humans.