MMP-2 in Periodontal Disease and Oral Cancer

申请人Bjorn Steffensen， DDS， MS, PhD，正在申请个人科学家奖（K02），以支持他的研究事业发展。该职业发展计划的目标是：1)扩展正在进行的研究，以确定抑制牙周病和口腔癌相关酶的方法；2)获得新的蛋白质组学技术的新知识和技能，以加强正在进行和未来的研究；3)发展成为一个富有成效和独立的科学家，具有动态和进步的研究计划，专注于伤口愈合，牙周病和口腔癌的机制。

DESCRIPTION (provided by applicant): The applicant, Bjorn Steffensen, DDS, MS, PhD, is applying for the Individual Scientist Award (K02) to support his research career development. The goals of this career development program are to: 1) Extend the ongoing research to identify approaches to inhibit enzymes involved in periodontal disease and oral cancer, 2) Gain new knowledge and skills on novel proteomics technologies to strengthen ongoing and future research, and 3) Evolve into a productive and independent scientist with a dynamic and progressive research program focused on the mechanisms of wound healing, periodontal disease, and oral cancer. The research plan addresses the mechanism by which matrix metalloproteinase-2 (MMP-2) degrades tissues. The MMP-2 belongs to the matrix metalloproteinase family of enzymes, which collectively can degrade most tissue components. The MMPs are beneficial features of normal development and tissue adaptation, but uncontrolled MMP-2 activity has been associated strongly with inflammatory diseases, cancer, and poor wound healing. The proposal is designed to develop compounds that can specifically inhibit MMP-2. Since cleavage by the MMP-2 requires binding of the substrate molecules, we propose to investigate the mechanism by which MMP-2 binds its main collagen substrate. In collaboration with other scientists, molecular biology and protein structural analyses are combined to first screen random peptide libraries for interaction with the collagen-binding domain (CBD) of MMP-2 and map the MMP-2 binding sites on collagen. Subsequent nuclear magnetic resonance structural studies will identify the collagen binding site on the MMP-2 using complexes containing the CBD from MMP-2 and collagen-like peptides. The specific interactions will be verified by introducing specific mutations into the identified binding site. Subsequently the bioactivity of the synthetic peptides will be enhanced by structure-based modifications. Subsequent experiments will determine whether the synthetic bioactive synthetic peptides and binding site regions may inhibit MMP-2 and alter the behavior of cells in cultures. The studies will integrate novel proteomics approaches to fully understand the mechanisms by which such peptides and binding site regions influence cell behavior. The proposed studies should define the specific binding sites of MMP-2 and collagen and explore a new strategy to inhibit MMP-2 in periodontal disease and oral cancer.