: The small leucine-rich repeat proteoglycans, decorin and biglycan, are biological modulators of extracellular matrix assembly and cell growth in health and diverse pathological conditions such as cancer and fibrotic disease Our central hypothesis is that these closely related members of the small leucine-rich proteoglycan family are multifunctional glycoconjugates that exert their regulatory effects by simultaneously acting on several targets, including: (1) binding to collagen and regulating the temporal and spatial kinetics of fibrillogenesis; (2) modulating the activity and availability of TGF-b, a cytokine that regulates cell proliferation, cell migration, and synthesis of matrix components; and (3) interacting with the epidermal growth factor receptor and thereby modulating cell proliferation. We have shown that the complex folding and post-translational processing of decorin and biglycan are critical to many of their functions. Furthermore, it is clear that the multitude of in vitro activities ascribed to decorin and biglycan may not be physiologically relevant in vivo, and the therapeutic potential of these molecules in fibrotic disease and cancer will only be realized by a systematic approach that demonstrates a direct link between biological activity and physiological response. The goal of this research is to advance understanding of decorin and biglycan biology by elucidating molecular mechanisms by which they regulate extracellular matrix assembly, matrix deposition, and cell growth. We will investigate and characterize in detail the interaction with type I collagen, modulation of TGF-b activity, and influence on EGF-receptor controlled suppression of cell growth. We will map specific binding sites through generation of recombinant proteoglycans, core proteins, decorin-biglycan chimeras, and leucine-rich repeat replacement mutants, wherein the native structure is maintained but specific protein binding domains are disrupted.
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