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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 牙周韧带（PDL）的完整性对于口腔健康至关重要。富含胶原蛋白组织的炎症降解的牙周疾病会导致牙龈粘附和事件牙齿丢失。此外，牙周疾病经常与心血管疾病，糖尿病和早产有关。因此，口腔健康研究的积极领域是对PDL中胶原蛋白维持和修复重要因素的表征。 SPARC是一种分泌的胶原蛋白结合蛋白，具有反粘附和抗增殖活性。通过通过转基因小鼠确定的有效胶原蛋白沉积和稳定的积累，需要SPARC，这些小鼠不表达SPARC，而SPARC暴露了组织中胶原蛋白量的显着下降。我们已经证明了SPARC-NULL小鼠的PDL胶原蛋白的降低相似。我们假设SPARC功能结合胶原蛋白I，从而减少与细胞表面受体的相互作用，从而使胶原I稳定地掺入细胞外基质（ECM）中。在没有SPARC的情况下，我们预测由PDL成纤维细胞产生的胶原蛋白表现出增加胶原受体的参与度增加，导致胶原蛋白快速内在化，而ECM沉积为代价。因此，SPARC被暗示是胶原蛋白周转的关键调节剂。由于PDL表现出体内胶原蛋白周转的最高速率之一，因此该组织是表征SPARC功能的理想环境。在该提案的目标1中，我们将在随着时间的流逝而没有体内的SPARC，对PDL的胶原蛋白i沉积的影响。 AIM 2中概述的实验将确定SPARC表达是否会在体外降低PDL成纤维细胞的胶原蛋白摄取，并且这种摄取是否取决于整联蛋白€2€1接收器。 AIM 3探讨了与衰老相关的SPARC表达的增加是否有助于胶原蛋白的周转率降低和降低的增殖速率，指示来自老年PDL的成纤维细胞。这些特定目标的完成将为稳固的基础，以在保留和维持PDL的胶原蛋白结构完整性的关键要素中建立生产性研究线。