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）：在一系列细胞信号事件中，插科打已成为关键信号分子。尽管皮肤硫酸盐（DS）是皮肤和伤口液中最丰富的插科打术，但这代表了伤口愈合的区域，通过评估修复所需的细胞信号事件，尚待更广泛地评估。 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，而不是研究更广泛研究的GAG，硫酸乙酰肝素（HS）。这项研究的目的是进一步表征DS在体外对成纤维细胞生长因子信号传导的影响，并将这些发现推断为人类生理环境。总体假设是，FGF-10和FGF-22比HS更喜欢DS，并且伤口环境中DS结合蛋白的种群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是否比FGF10和FGF-22介导的信号传导中的DS优先。将评估依赖DS的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旨在评估人的伤口液，以通过体内分子进近识别HS更强结合DS的FGF。另外，将评估DS对FGF定位和伤口闭合的影响。提出的实验将阐明DS在最佳组织修复所需的FGF细胞信号传导事件中的作用，并表征DS结合蛋白的表达模式，最终可以用作病理疾病中的诊断标记。在临床上，有人提出插科打术在皮肤病的发病机理中起作用。基本FGFR2-IIIB配体对DS的依赖性预测，DS合成或降解的疾病会破坏正常的伤口修复。具体而言，我们怀疑异常伤口中存在的DS平衡与正常修复过程中观察到的DS的平衡会有所不同，这是一些临床研究支持的。因此，对正常或患病个体的人伤口液中DS的水平和/或硫酸化的分析是该研究建议的前瞻性临床方向，该方向可能产生一种诊断工具，用于诊断伤口愈合异常，并采用新的治疗方法来促进正常伤口修复。总体而言，提出的技术允许暴露于新的分子和生化方法，以分析真皮伤口愈合中蛋白质和碳水化合物功能以及先天免疫。