(Taken from the application's abstract): The overall goal of this research proposal is to determine the functions and the mechanism of action of three novel amine oxidases, LOXL, LOXL2 and LOXL3 that are structurally and functionally related to lysyl oxidase (LOX). LOX is a copper-dependent amine oxidase that has been known for many years to be responsible for the catalysis of lysine-derived cross-links in the extracellular matrix proteins, elastin and collagen. Alterations in the synthesis and activity of LOX are known to be associated with a variety of acquired and heritable diseases, including skin disorders such as cuffs laxa, Wilson's and Menkes disease. In an attempt to determine the precise role of LOX in such diverse pathologies, these investigators have recently shown that LOX is not just a single enzyme but rather a family of at least four functionally- related but genetically-distinct lysyl oxidases. From preliminary data presented in this application, it is clear that these lysyl oxidases (referred to as lysyl oxidase-like or LOXL proteins) are found in different tissues in both extracellular and intracellular locations. This new family of enzymes therefore has related but distinct functions in different tissues and the work proposed in this application is intended to elucidate some of the functions of these new lysyl oxidases. The role of lysyl oxidase in human disorders, either as a primary determinant of a disease process or as a secondary consequence to other genetic or environmental factors, has never been clear. By providing, for the first time, information describing the complex role of a family of lysyl oxidases in tissue structure and function, they hope to provide new and valuable insight into the precise mechanism(s) by which these critical amine oxidases influence a variety of different disease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Minority Biomedical Research Support Thematic Project Grants (S11)
Project #
5S11AR047713-03
Application #
6632782
Study Section
Special Emphasis Panel (ZAR1-JRL-C (J1))
Program Officer
Lamar, Charisee A
Project Start
2001-04-20
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$335,671
Indirect Cost
Name
University of Hawaii
Department
Type
Organized Research Units
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Szauter, K M; Ordas, A; Laxer, R M et al. (2010) A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network. Br J Dermatol 163:1102-15
Postovit, Lynne-Marie; Abbott, Daniel E; Payne, Stacey L et al. (2008) Hypoxia/reoxygenation: a dynamic regulator of lysyl oxidase-facilitated breast cancer migration. J Cell Biochem 103:1369-78
Cao, Tongyu; Racz, Peter; Szauter, Kornelia M et al. (2007) Mutation in Mpzl3, a novel [corrected] gene encoding a predicted [corrected] adhesion protein, in the rough coat (rc) mice with severe skin and hair abnormalities. J Invest Dermatol 127:1375-86
Jansen, Matthias K; Csiszar, Katalin (2007) Intracellular localization of the matrix enzyme lysyl oxidase in polarized epithelial cells. Matrix Biol 26:136-9
Laczko, R; Szauter, K M; Jansen, M K et al. (2007) Active lysyl oxidase (LOX) correlates with focal adhesion kinase (FAK)/paxillin activation and migration in invasive astrocytes. Neuropathol Appl Neurobiol 33:631-43
Polgar, Noemi; Fogelgren, Ben; Shipley, J Michael et al. (2007) Lysyl oxidase interacts with hormone placental lactogen and synergistically promotes breast epithelial cell proliferation and migration. J Biol Chem 282:3262-72
Fogelgren, Ben; Polgar, Noemi; Szauter, Kornelia Molnarne et al. (2005) Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. J Biol Chem 280:24690-7
Rajkumar, Vineeth S; Howell, Kevin; Csiszar, Katalin et al. (2005) Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 7:R1113-23
Thomassin, Laetitia; Werneck, Claudio C; Broekelmann, Thomas J et al. (2005) The Pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers. J Biol Chem 280:42848-55
Szauter, Kornelia Molnarne; Cao, Tongyu; Boyd, Charles D et al. (2005) Lysyl oxidase in development, aging and pathologies of the skin. Pathol Biol (Paris) 53:448-56

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