Matrix metalloproteinases (MMP) are a class of enzymes that degrade extracellular matrix in vitro and are upregulated in cancer, inflammation, and other human pathologies. Although inhibitor studies have been tested in clinical trials, they have not been effective against cancer and have had unacceptable side effects. These failed trials indicate that before effective therapies can be designed, the scientific community needs a more complete understanding of MMP biology and their normal physiological roles: what their functions are and what substrates they cleave. However, because there are 22 MMPs in mice and they can compensate for each other's loss, mutant analysis in mice does not give complete information about function. The fruitfly, Drosophila melanogaster, is an ideal organism for the study of MMPs, because they have only two MMPs in their genome. Previously mutations were generated in both genes, and the mutants have specific phenotypes indicating that the genes are non-redundant. In preliminary studies, two-hybrid screening identified candidate proteins that specifically bind to the dMmp1 hemopexin domain, and the physical interaction with one candidate has been confirmed by co-immunoprecipitation.
In Specific Aim 1, the relationship between this candidate and dMmp1 will be determined in culture, in vitro, and in vivo;in preliminary studies, it appears to be proteolyzed in an Mmp1 -specific manner. Both Mmp1 and the candidate interactor may be important for the animal's response to septic wounding, and their roles in septic wound healing will be determined in Specific Aim 2. To gain a better understanding of MMP function in vivo, the cellular functions of the dMmp1 and its C-terminal hemopexin domain will be identified in the tracheal system in Specific Aim 3. (for lay people:) In order to grow and metastasize, cancers are believed to rely on proteins that break down and remodel body tissues. One such protein family, called MMPs, has been targeted by pharmaceutical companies for designing anti-cancer drugs, but these have had crippling side effects because we do not understand what MMPs normally do in the body. We will identify the functions and mechanisms of an MMP in a simple model organism in the hopes of learning how to make better cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM073883-05
Application #
7924891
Study Section
Development - 1 Study Section (DEV)
Program Officer
Flicker, Paula F
Project Start
2006-09-25
Project End
2012-07-31
Budget Start
2010-09-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$268,051
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ramos-Lewis, William; LaFever, Kimberly S; Page-McCaw, Andrea (2018) A scar-like lesion is apparent in basement membrane after wound repair in vivo. Matrix Biol 74:101-120
Ramos-Lewis, William; Page-McCaw, Andrea (2018) Basement membrane mechanics shape development: Lessons from the fly. Matrix Biol :
LaFever, Kimberly S; Wang, Xiaoxi; Page-McCaw, Patrick et al. (2017) Both Drosophila matrix metalloproteinases have released and membrane-tethered forms but have different substrates. Sci Rep 7:44560
Wang, Xiaoxi; Page-McCaw, Andrea (2014) A matrix metalloproteinase mediates long-distance attenuation of stem cell proliferation. J Cell Biol 206:923-36
McCall, A Scott; Cummings, Christopher F; Bhave, Gautam et al. (2014) Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture. Cell 157:1380-92
Saito-Diaz, Kenyi; Chen, Tony W; Wang, Xiaoxi et al. (2013) The way Wnt works: components and mechanism. Growth Factors 31:1-31
Broderick, Sarah; Wang, Xiaoxi; Simms, Nicholas et al. (2012) Drosophila Ninjurin A induces nonapoptotic cell death. PLoS One 7:e44567
Stevens, Laura J; Page-McCaw, Andrea (2012) A secreted MMP is required for reepithelialization during wound healing. Mol Biol Cell 23:1068-79
Schmidt, Rebecca L; Rinaldo, Francesca M; Hesse, Shayla E et al. (2011) Cleavage of PGRP-LC receptor in the Drosophila IMD pathway in response to live bacterial infection in S2 cells. Self Nonself 2:125-141
Miller, Crystal M; Liu, Nan; Page-McCaw, Andrea et al. (2011) Drosophila MMP2 regulates the matrix molecule faulty attraction (Frac) to promote motor axon targeting in Drosophila. J Neurosci 31:5335-47

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