CALPROTECTIN AS A MOLECULAR SENSOR AND REGULATOR OF OXIDATION IN WOUND HEALING

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DESCRIPTION (provided by applicant): The objective of this application is for Dr. Sroussi to expand on his doctoral training and lay the foundation for a self-sustaining, long-term investigational program as a tenure-track faculty member. The training aspect of the award will be under the guidance of a mentor and an advisory committee. Dr. Phillip Marucha will mentor the candidate in all aspects of becoming a successful independent research faculty including: developing an internationally recognized competitive research program; significantly advancing knowledge in Oral Health Science; collaborating within an interdisciplinary team; and ultimately obtaining a project grant (R01) to support an independent research team. This program will also include formal and practical training in the ethical conduct of research, and clinical research. The College of Dentistry will provide a full range of additional support including access to equipment, matching start-up funds, as well as a rich nurturing research environment within a comprehensive academic health sciences center. Dr. Sroussi proposes to build upon his previous work on calprotectin, a pleiotropic and functionally non-redundant protein complex that is highly expressed during wound healing. He will study its oxidation and test its relevance in an experimental model of stress-impaired wound healing in which the role of oxygen was previously established. Redox imbalance in this model results in oxidative stress which may trigger deleterious inflammation, metabolic deregulation, deficient angiogenesis and impaired wound healing. Work done by others and expanded by Dr. Sroussi has shown that calprotectin regulates oxidation, leukocyte recruitment and cell metabolism in a manner controlled by its own oxidative state. The study hypothesis is that calprotectin is a molecular sensor of redox conditions which influences the outcomes of wound healing. The research project will address in its first two aims the effects of calprotectin and its oxidation over 2 crucial aspects of wound healing: the neutrophil oxidative burst, which is important in antimicrobial activity; and the proliferation of catabolic cells, which is important in replacing damaged tissue. The third aim of this proposal will directly address the biological relevance of calprotectin by testing its effect under different oxidative conditions on wound healing in an established mouse model of restraint stress. In this model restraint impairs oxygen supply to the wound, resulting in oxidative stress and altered healing. The ability of oxidized calprotectin molecules to accelerate wound healing and eliminate the effect of restraint stress will be tested. Understanding the role of calprotectin in the context of redox biology will result in the development of targeted therapeutics with broad beneficial medical impact. Aging, diabetes or stress results in poor oxygen supply to wounds and in slow or failed healing. We are studying this observation and testing a strategy to improve wound healing.