COBRE P6: FUNCT OF SPARC IN THE REGULATION OF COLLAGEN IN THE PERIODONTAL LIGAM

COBRE P6：SPARC 在牙周韧带中胶原蛋白调节中的功能

• 批准号: 7720805
• 负责人: Amy D Bradshaw
• 金额: $ 12.73万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720805
• 关键词: Adhesions; Adhesives; Aging; Area; Binding; Binding Proteins; Cardiovascular Diseases; Cell Surface Receptors; Collagen; Collagen Receptors; Computer Retrieval of Information on Scientific Projects Database; Deposition; Diabetes Mellitus; Elements; Exhibits; Extracellular Matrix; Fibroblasts; Foundations; Funding; Gingiva; Grant; In Vitro; Inflammatory; Institution; Integrins; Knockout Mice; Lead; Maintenance; Oral health; Periodontal Diseases; Periodontal Ligament; Premature Birth; Rate; Regulation; Research; Research Personnel; Resources; Solid; Source; Time; Tissues; Tooth Loss; Transgenic Mice; United States National Institutes of Health; aged; in vivo; receptor; repaired; research study; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Integrity of the periodontal ligament (PDL) is imperative for oral health. Periodontal disease typified by inflammatory degradation of this collagen-rich tissue can lead to loss of gingival adhesion and eventual tooth loss. In addition, periodontal disease is frequently associated with cardiovascular disease, diabetes, and preterm births. Hence, an active area of oral health research is the characterization of factors important for the maintenance and repair of collagen in the PDL. SPARC is a secreted collagen-binding protein with counter-adhesive and anti-proliferative activity. SPARC is required for efficient collagen deposition and stable accumulation as established by virtue of transgenic mice that do not express SPARC that exhibit significant decreases in amounts of collagen in tissues. We have demonstrated a similar reduction in collagen in the PDL of SPARC-null mice. We hypothesize that SPARC functions to bind collagen I and thereby diminish collagen interaction with cell-surface receptors that allows for stable incorporation of collagen I into the extracellular matrix (ECM). In the absence of SPARC, we predict that collagen produced by PDL fibroblasts exhibits increased engagement of collagen receptors leading to rapid internalization of collagen at the expense of ECM deposition. Therefore, SPARC is implicated as a key regulator of collagen turnover. As PDL exhibits one of the highest rates of collagen turnover in the body, this tissue is an ideal milieu in which to characterize SPARC function. In Aim 1 of this proposal, we will characterize the effects on collagen I deposition in the PDL in the absence of SPARC in vivo over time. Experiments outlined in Aim 2 will determine whether SPARC expression reduces collagen uptake by PDL fibroblasts in vitro and whether this uptake is dependent upon integrin ¿2¿1 receptor. Aim 3 explores whether increased expression of SPARC associated with aging contributes to reduced collagen turnover and lower rates of proliferation indicative of fibroblasts from aged PDL. Completion of these Specific Aims will provide a solid foundation on which to build a productive line of research into a critical element that preserves and maintains collagen structural integrity of the PDL.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 牙周膜(PDL)的完整性对口腔健康至关重要。以富含胶原蛋白的组织的炎症降解为特征的牙周病会导致牙龈粘附性丧失，最终导致牙齿脱落。此外，牙周病经常与心血管疾病、糖尿病和早产有关。因此，口腔健康研究的一个活跃领域是表征对PDL中胶原的维持和修复至关重要的因素。SPARC是一种分泌型胶原结合蛋白，具有抗黏附和抗增殖活性。由于转基因小鼠不表达SPARC，而组织中的胶原蛋白数量显著减少，因此SPARC是有效的胶原沉积和稳定积累所必需的。我们已经在SPARC基因缺失的小鼠的PDL中发现了类似的胶原减少。我们假设SPARC的功能是结合I型胶原，从而减少胶原与细胞表面受体的相互作用，从而允许I型胶原稳定地结合到细胞外基质(ECM)中。在没有SPARC的情况下，我们预测PDL成纤维细胞产生的胶原与胶原受体的结合增加，导致胶原的快速内化，但以细胞外基质沉积为代价。因此，SPARC被认为是胶原蛋白周转的关键调节因子。由于PDL是体内胶原转换率最高的组织之一，该组织是表征SPARC功能的理想环境。在这项建议的目标1中，我们将描述在体内没有SPARC的情况下，随着时间的推移，对PDL中I型胶原沉积的影响。AIM 2中概述的实验将确定SPARC的表达是否会减少体外培养的PDL成纤维细胞对胶原的摄取，以及这种摄取是否依赖于整合素2受体。目的3探讨随着年龄的增长，SPARC的表达增加是否导致老年PDL成纤维细胞的胶原转换率和增殖率降低。这些特定目标的完成将提供坚实的基础，在此基础上建立一条富有成效的研究路线，成为保存和维护PDL胶原结构完整性的关键因素。