SPARC is a matricellular protein that functions through disruption of cell-matrix interactions. As such, it provides a structurally characterized prototype for this newly defined class of regulatory macromolecules. The expression of SPARC in remodeling tissues, as a consequence of normal development or response to injury, coupled with its multiple regulatory effect on cultured endothelial cells, has been consistent with our proposal that SPARC subserves a fundamental role in vascular morphogenesis and cellular differentiation. The process of blood vessel growth encompasses several discrete but often coincident endpoints which endothelial cells must achieve for the genesis of an intact vascular bed. At which of these points does SPARC function? From recent studies on cultured endothelial cells, this laboratory has shown that SPARC acts initially as a counteradhesive protein through a pathway dependent on tyrosine phosphorylation, and distally as an inhibitor of the cell cycle. Other levels of regulation that are potentially important are a) abrogation of the mitogenic effect of vascular endothelial growth factor (VEGF) on the endothelial cell cycle through a direct interaction with SPARC , and b) proteolysis of SPARC into bioactive peptides. They propose that SPARC alters the kinetics of the interrelationship among endothelial cells, mitogens, and extracellular matrix, and thus predisposes the endothelium toward an activated state requisite for vascular growth. This renewal application addresses the structural and mechanistic correlates of SPARC function at specific stages of vascular morphogenesis in vivo and in vitro. The proposed experiments should result in a more precise understanding of how vessels grow in the context of signals mediated by the matricellular protein SPARC , a dynamic resident of the extracellular space.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM040711-10
Application #
2398116
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-07-01
Project End
2001-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
10
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cheng, Lamei; Sage, E Helene; Yan, Qi (2013) SPARC fusion protein induces cellular adhesive signaling. PLoS One 8:e53202
Millecamps, Magali; Tajerian, Maral; Naso, Lina et al. (2012) Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice. Pain 153:1167-79
Kucukdereli, Hakan; Allen, Nicola J; Lee, Anthony T et al. (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci U S A 108:E440-9
Nie, Jing; Bradshaw, Amy D; Delany, Anne M et al. (2011) Inactivation of SPARC enhances high-fat diet-induced obesity in mice. Connect Tissue Res 52:99-108
Workman, Gail; Sage, E Helene (2011) Identification of a sequence in the matricellular protein SPARC that interacts with the scavenger receptor stabilin-1. J Cell Biochem 112:1003-8
Millecamps, Magali; Tajerian, Maral; Sage, E Helene et al. (2011) Behavioral signs of chronic back pain in the SPARC-null mouse. Spine (Phila Pa 1976) 36:95-102
Weaver, Matt; Workman, Gail; Schultz, Chad R et al. (2011) Proteolysis of the matricellular protein hevin by matrix metalloproteinase-3 produces a SPARC-like fragment (SLF) associated with neovasculature in a murine glioma model. J Cell Biochem 112:3093-102
Weaver, Matt S; Workman, Gail; Cardo-Vila, Marina et al. (2010) Processing of the matricellular protein hevin in mouse brain is dependent on ADAMTS4. J Biol Chem 285:5868-77
Arnold, Shanna A; Rivera, Lee B; Miller, Andrew F et al. (2010) Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3:57-72
Nie, Jing; Sage, E Helene (2009) SPARC inhibits adipogenesis by its enhancement of beta-catenin signaling. J Biol Chem 284:1279-90

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