DECORIN AND BIGLYCAN: STRUCTURE AND FUNCTION

描述（改编自申请人的摘要：富含亮氨酸的小重复序列 蛋白聚糖、核心蛋白聚糖和双糖蛋白聚糖是细胞外基质的生物调节剂， 健康和不同病理条件下的基质组装和细胞生长 例如癌症和纤维化疾病。我们的中心假设是， 富含亮氨酸的小蛋白聚糖家族的密切相关的成员是 多功能糖缀合物通过以下方式发挥其调节作用： 同时作用于多个靶点，包括：（1）与胶原蛋白结合 调控纤维形成的时空动力学;（2） 调节TGF-β的活性和可用性，TGF-β是一种细胞因子， 细胞增殖、细胞迁移和基质成分的合成;和（3） 与表皮生长因子受体相互作用， 细胞增殖 我们已经表明，复杂的折叠和翻译后加工的 核心蛋白聚糖和双糖链蛋白聚糖对于它们的许多功能是关键的。而且 很明显，核心蛋白聚糖的多种体外活性， 双糖链蛋白聚糖在体内可能不是生理学相关的， 这些分子在纤维化疾病和癌症中的潜力将仅限于 通过系统的方法实现，证明了 生物活性和生理反应。 本研究的目的是促进对核心蛋白聚糖和biglycan的理解， 通过阐明它们调节的分子机制， 细胞外基质组装、基质沉积和细胞生长。我们将 详细研究和表征与I型胶原的相互作用， TGF-β活性的调节，以及对EGF受体控制的影响 抑制细胞生长。我们将绘制特定的结合位点， 重组蛋白聚糖、核心蛋白、核心蛋白聚糖-双糖蛋白聚糖的产生 嵌合体和富含亮氨酸的重复置换突变体，其中天然的 结构得以保持，但特异性蛋白质结合结构域被破坏。

DESCRIPTION (Adapted from applicant's abstract : 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.