Diabetes-enhanced Experimental Periodontitis

描述(由申请人提供)：2型糖尿病显著增加牙周疾病的风险和严重程度。在人类中，已经提出了两种不同的牙周病模型，一种是慢性连续模型，另一种是随机爆发模型。目前的证据不能排除其中之一。我们将使用一种结扎诱导的大鼠牙周骨丢失模型，该模型表现出与随机破裂模型一致的特征。结扎可促进细菌对结缔组织的侵袭，导致细胞因子表达增加、结缔组织附着丧失、靠近骨的炎细胞聚集和牙槽骨吸收。初步数据表明，在大鼠结扎模型中，糖尿病显著改变了牙周破坏的进程，这与糖尿病对人类牙周组织的已知影响是一致的。当结扎被移除时，与基因匹配的正常血糖瘦身对照组相比，2型Zucker糖尿病肥胖大鼠有一段与骨连接相关的骨形成时期显着减少。该模型的一个显著优点是骨吸收和骨形成的周期都是已知的，并且可以分别量化。因此，可以准确地评估以下研究所需的两个关键变量。为了保持骨量的偶联，确保骨吸收后的骨形成。糖尿病可能通过抑制糖尿病受损的骨形成所致的偶联来增加牙槽骨的丢失。因此，我们将集中在一个以前未报道的方面，即糖尿病干扰了一次骨吸收后新牙槽骨的形成。这项研究的目的是调查一种假说，即糖尿病通过促进肿瘤坏死因子-D的产生而增加细胞凋亡，从而干扰牙槽骨吸收和形成的耦合。目的1将研究糖尿病动物牙周组织的解偶联是否是由于肿瘤坏死因子-D水平升高所致。这些研究将使用肿瘤坏死因子特异性抑制剂，由I.P.应用依那西普。注射研究肿瘤坏死因子-Q目标2的作用将确定糖尿病促进的细胞凋亡是否是牙周组织骨形成和吸收解偶联的重要功能机制。这些研究将使用I.P.在大鼠牙周骨吸收模型中注射半胱氨酸天冬氨酸氨基转移酶抑制剂阻断骨形成过程中的细胞凋亡。目的3研究肿瘤坏死因子是否在糖尿病促进成纤维细胞凋亡中起关键作用，糖尿病改变的基因表达是由mRNA谱和基质金属蛋白酶活性决定的。这些研究将使用目标1中描述的大鼠模型和肿瘤坏死因子阻滞剂。

DESCRIPTION (provided by applicant): Type 2 diabetes significantly increases the risk and severity of periodontal disease. In humans two different models have been proposed for periodontal disease, a chronic continuous model and a random burst model. Current evidence does not rule out one or the other. We will use a ligature induced model of periodontal bone loss in the rat that exhibits features consistent with the random burst model. The ligature facilitates bacterial invasion of connective tissue leading to an increase in cytokine expression, loss of connective tissue attachment, inflammatory cell recruitment close to bone and alveolar bone resorption. Preliminary data indicate that diabetes significantly alters the progression of periodontal destruction in the rat ligature model in a way that is consistent with the known impact of diabetes on the human periodontium. When ligatures are removed there is a period of bone formation associated with osseous coupling that is significantly reduced in type 2 Zucker diabetic fatty rats compared to genetically matched normoglycemic lean controls. A significant advantage of this model is that the period of bone resorption and formation are both known and can be quantified separately. Thus, the two critical variables needed for the studies below can be accurately assessed. In order to maintain bone mass coupling ensures that bone formation follows resorption. It is possible that diabetes enhances alveolar bone loss by suppression of coupling due to diabetes-impaired bone formation. Thus, we will focus on a previously unreported aspect, that diabetes interferes with the formation of new alveolar bone following an episode of bone resorption. The goal of the proposed studies is to investigate a hypothesis that diabetes through enhanced production of TNF-D increases apoptosis and thereby interferes with coupling of alveolar bone resorption and formation. Aim 1 will investigate whether uncoupling in the periodontium of diabetic animals is due to enhanced levels of TNF-D. These studies will use a TNF-specific inhibitor, etanercept applied by i.p. injection to study the role of TNF-Q Aim 2 will determine whether diabetes enhanced apoptosis represents a functionally significant mechanism for uncoupling of bone formation and resorption in the periodontium. These studies will use i.p. injection of a caspase inhibitor to block apoptosis during bone formation following an episode of periodontal bone resorption in the rat ligature model. Aim 3 will study whether TNF plays a critical role in diabetes enhanced fibroblast apoptosis, diabetes altered gene expression determined by mRNA profiling and matrix metalloproteinase activity. These studies will use the rat model and TNF blocker described in Aim 1.