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 蛋白多糖、核心蛋白聚糖和二聚糖是细胞外的生物调节剂。 健康和多种病理条件下的基质组装和细胞生长 比如癌症和纤维性疾病我们的中心假设是这些 富含亮氨酸的蛋白多糖家族的近亲成员是 通过以下途径发挥其调节作用的多功能糖结合物 同时作用于几个靶点，包括：(1)与胶原结合 调控纤维形成的时空动力学；(2) 调节细胞因子转化生长因子-β的活性和可用性 细胞增殖、细胞迁移和基质成分的合成； 与表皮生长因子受体相互作用，从而调节 细胞增殖。 我们已经证明，复杂的折叠和后平移处理 核心蛋白和双聚糖对它们的许多功能都是至关重要的。此外，它还 很明显，大量的体外活动归因于装饰素和 Biglycan在体内可能没有生理上的相关性，而治疗 这些分子在纤维化疾病和癌症中的潜力只会是 通过一种系统的方法来实现，该方法证明了 生物活性和生理反应。 本研究的目的是增进对核心蛋白和二聚糖的了解。 通过阐明它们调节的分子机制来实现生物学 细胞外基质组装、基质沉积和细胞生长。我们会 详细研究和表征与I型胶原的相互作用， 转化生长因子-β活性的调节及其对表皮生长因子受体调控的影响 抑制细胞生长。我们将通过以下方式绘制特定的结合位点 重组蛋白多糖、核心蛋白、核心蛋白-二聚糖的制备 嵌合体和富含亮氨酸的重复序列替换突变体，其中原生的 结构保持不变，但特定的蛋白质结合域被破坏。

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.