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Title page for ETD etd-03132012-101745


Type of Document Dissertation
Author Stevens, Laura Jeanette
Author's Email Address laurajstevens@gmail.com
URN etd-03132012-101745
Title The Regulation and Essential Functions of Matrix Metalloproteinases during Wound Healing
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
David Miller Committee Chair
Andrea Page-McCaw Committee Member
Jason Jesson Committee Member
Jeff Davidson Committee Member
Laura Lee Committee Member
Keywords
  • MMP
  • JNK
  • re-epithelialization
  • cell migration
Date of Defense 2012-02-28
Availability unrestricted
Abstract
Wound healing, an essential function to the survival of all multicellular organisms, requires the precise orchestration of multiple cell types in order to repair the damaged tissue. Wound healing involves three overlapping phases: inflammation, re-epithelialization, and scar formation. Matrix metalloproteinases (MMPs) are endopeptidases of the metzincin family, which have been shown to function throughout wound healing, but their precise functions and regulatory mechanisms are unclear in vivo largely due to the complications of redundancy. In mammals there are 24 MMPs (seventeen secreted type MMPs and seven membrane-anchored type MMPs). MMPs are inhibited by Tissue Inhibitors of Metalloproteinases (TIMP), of which there are four in mammals. To bypass the complications of redundancy, we utilized Drosophila melanogaster as a model system to study MMPs in vivo during wound healing. Drosophila serve as a simple system to not only study wound healing, but the Drosophila genome encodes only two MMPs, one secreted (Mmp1) and one membrane-anchored (Mmp2), providing a system to elucidate the functions of each MMP class in vivo. Our results indicate that Mmp1 and Mmp2, as well as the inhibitor, Timp are required for re-epithelialization, where they may function together to promote cell migration. During re-epithelialization, Mmp1, under the control of the JNK signaling pathway, functions to promote cell migration by facilitating collagen IV remodeling, promoting actin cytoskeleton reorganization, and inducing RTK signaling. Mmp1 from the hemocytes may function to limit the area of both JNK and RTK signaling to the immediate vicinity of the wound. Preliminary results suggest that Mmp1 and Mmp2 may regulate hemostasis and the melanization cascade, as we observe both clotting and melanization defects in Mmp1 and Mmp2 mutants. In unwounded tissue, both Mmp1 and Timp are required for basement membrane maintenance, a function they do not share with Mmp2. The combination of both shared and independent phenotypes between Mmp1, Mmp2, and Timp mutants suggest that Mmp1, Mmp2, and Timp may form a complex to promote wound healing; however, if such a complex does form in vivo it is context-specific.
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