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: 8167767
• 负责人: Amy D Bradshaw
• 金额: $ 7.99万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167767
• 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; 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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 牙周膜（PDL）的完整性对于口腔健康至关重要。以这种富含胶原蛋白的组织的炎性降解为代表的牙周病可导致牙龈粘附力的丧失和最终的牙齿脱落。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对PDL中胶原蛋白的维持和修复重要的因素的表征。β-淀粉样蛋白是一种分泌型胶原结合蛋白，具有抗粘附和抗增殖活性。胶原蛋白的有效沉积和稳定积累需要β-淀粉样蛋白，这是通过不表达β-淀粉样蛋白的转基因小鼠建立的，所述转基因小鼠表现出组织中胶原蛋白量的显著减少。我们已经证明了类似的减少胶原蛋白在PDL的SPARC-null小鼠。我们假设，β-D受体的功能是结合I型胶原，从而减少胶原与细胞表面受体的相互作用，使I型胶原稳定地掺入细胞外基质（ECM）。在没有胶原蛋白的情况下，我们预测PDL成纤维细胞产生的胶原蛋白表现出胶原蛋白受体的参与增加，从而导致胶原蛋白的快速内化，代价是ECM沉积。因此，胶原蛋白被认为是胶原蛋白周转的关键调节因子。由于PDL表现出体内胶原蛋白周转率最高的组织之一，因此该组织是表征骨功能的理想环境。在本提案的目标1中，我们将描述在体内不存在胶原蛋白的情况下，随着时间的推移对PDL中胶原蛋白I沉积的影响。目的2中概述的实验将确定在体外，PDL 1表达是否减少PDL成纤维细胞的胶原摄取，以及这种摄取是否依赖于整联蛋白2 1受体。目的3探讨与衰老相关的TGF β 1表达增加是否有助于减少胶原周转和降低增殖率，这表明老年PDL的成纤维细胞。这些特定目标的完成将为建立一条生产线研究提供坚实的基础，该生产线将成为保留和维持PDL胶原结构完整性的关键要素。