Dermatan sulfate and its role in tissue repair

硫酸皮肤素及其在组织修复中的作用

• 批准号: 7405689
• 负责人: Katherine Amanda Radek
• 金额: $ 5.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405689
• 关键词: Area; Binding; Binding Proteins; Biochemical; Carbohydrates; Cell Proliferation; Cells; Clinical; Clinical Research; Closure; Cutaneous; Defect; Dependence; Dermal; Dermatan Sulfate; Diagnostic; Disease; Elderly; Equilibrium; Event; Excision; Exposure to; FGF10 gene; Fellowship; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Glycosaminoglycans; Goals; Growth Factor; Healed; Heparitin Sulfate; Human; In Vitro; Individual; Investigation; Laboratories; Lead; Ligands; Liquid substance; Mediating; Methods; Mitogen-Activated Protein Kinases; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathologic; Patients; Pattern; Physiological; Play; Population; Protein Family; Proteins; Purpose; Regulation; Research; Research Proposals; Risk; Role; Signal Transduction; Signaling Molecule; Skin; Specificity; Structure; Techniques; Therapeutic; Training; Wound Healing; base; cytokine; design; diabetic; fibroblast growth factor 10; healing; in vivo; keratinocyte growth factor; member; migration; novel; novel therapeutics; prospective; receptor; repaired; research study; response; skin disorder; sulfation; tissue regeneration; tool; wound

DESCRIPTION (provided by applicant): GAGs have emerged as critical signaling molecules in an array of cell signaling events. Although dermatan sulfate (DS) is the most abundant GAG in the skin and in wound fluid, this represents an area of wound healing which remains to be more extensively evaluated through the assessment of cellular signaling events required for repair. DS has been shown to stimulate cellular proliferation via Fibroblast Growth Factor-2 (FGF-2) and FGF-7 mediated signaling more so than the more extensively studied GAG, heparan sulfate (HS). The purpose of this study is to further characterize the effect of DS on Fibroblast Growth Factor signaling in vitro, and extrapolate these findings to a human physiologic setting. The overall hypothesis is that FGF-10 and FGF-22 prefer DS over HS, and that the population of DS-binding proteins in the wound milieu can significantly influence tissue repair. In Aim I, we will determine if DS is preferred over HS in FGF10 and FGF-22 mediated signaling using an in vitro biochemical approach. The binding capability, proliferative capacity, and structural specificity of DS-dependent FGF/FGF receptor interactions will be assessed. Aim II is designed to evaluate human wound fluid to identify the FGFs that more strongly bind DS over HS through an in vivo molecular approach. In addition, the effect of DS on FGF localization and wound closure will be assessed. The proposed experiments will elucidate the role of DS in FGF-cell signaling events required for optimal tissue repair and characterize the expression patterns of DS-binding proteins, which can ultimately be used as a diagnostic marker in pathologic disease. Clinically, it has been suggested that GAGs play a role in the pathogenesis of skin disease. Finding a dependence for DS by the essential FGFR2-IIIB ligands would predict that a disorder of DS synthesis or degradation would disrupt normal wound repair. Specifically, we suspect that the balance of DS present in abnormal wounds will be different than that observed during normal repair, which is supported by a few clinical studies. Hence, the analysis of the levels and/or sulfation of DS in human wound fluid from normal or diseased individuals is a prospective clinical direction for this research proposal, which may yield a diagnostic tool for abnormal wound healing and novel therapeutic approaches to promote normal wound repair. Overall, the techniques proposed allow for exposure to new molecular and biochemical methods with which to analyze protein and carbohydrate function and innate immunity in dermal wound healing.

描述（由申请人提供）：GAG 已成为一系列细胞信号转导事件中的关键信号转导分子。尽管硫酸皮肤素 (DS) 是皮肤和伤口液中最丰富的 GAG，但这代表了伤口愈合的一个领域，仍有待通过评估修复所需的细胞信号事件进行更广泛的评估。 DS 已被证明可以通过成纤维细胞生长因子 2 (FGF-2) 和 FGF-7 介导的信号传导刺激细胞增殖，其效果比更广泛研究的 GAG、硫酸乙酰肝素 (HS) 更有效。本研究的目的是进一步表征 DS 对体外成纤维细胞生长因子信号传导的影响，并将这些发现外推到人体生理环境中。总体假设是 FGF-10 和 FGF-22 更喜欢 DS 而不是 HS，并且伤口环境中的 DS 结合蛋白群体可以显着影响组织修复。在目标 I 中，我们将使用体外生化方法确定在 FGF10 和 FGF-22 介导的信号传导中 DS 是否优于 HS。将评估 DS 依赖性 FGF/FGF 受体相互作用的结合能力、增殖能力和结构特异性。 Aim II 旨在评估人体伤口液，通过体内分子方法鉴定与 DS 结合更牢固的 FGF。此外，还将评估 DS 对 FGF 定位和伤口闭合的影响。拟议的实验将阐明 DS 在最佳组织修复所需的 FGF 细胞信号转导事件中的作用，并表征 DS 结合蛋白的表达模式，最终可用作病理疾病的诊断标记物。临床上，有人认为GAGs在皮肤病的发病机制中发挥作用。发现必需的 FGFR2-IIIB 配体对 DS 的依赖性将预测 DS 合成或降解的紊乱将破坏正常的伤口修复。具体来说，我们怀疑异常伤口中存在的 DS 平衡将不同于正常修复过程中观察到的 DS 平衡，这得到了一些临床研究的支持。因此，分析正常或患病个体的人体伤口液中 DS 的水平和/或硫酸盐化是本研究提案的一个前瞻性临床方向，这可能会产生异常伤口愈合的诊断工具和促进正常伤口的新治疗方法维修。总体而言，所提出的技术允许接触新的分子和生化方法，用于分析真皮伤口愈合中的蛋白质和碳水化合物功能以及先天免疫。