Diabetes-enhanced Experimental Periodontitis

描述（由申请人提供）：2型糖尿病显著增加牙周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，慢性连续模型和随机爆发模型。目前的证据并不排除其中一种。我们将在大鼠中使用结扎诱导的牙周骨丢失模型，其表现出与随机破裂模型一致的特征。结扎促进结缔组织的细菌侵入，导致细胞因子表达增加、结缔组织附着丧失、靠近骨的炎性细胞募集和牙槽骨吸收。初步数据表明，糖尿病显著改变大鼠结扎模型中牙周破坏的进展，其方式与糖尿病对人类牙周组织的已知影响一致。当结扎线被移除时，有一段与骨偶联相关的骨形成期，与遗传匹配的血糖正常的瘦对照相比，2型Zucker糖尿病肥胖大鼠的骨形成期显著减少。该模型的一个显著优点是骨吸收和骨形成的时间都是已知的，并且可以单独量化。因此，可以准确评估以下研究所需的两个关键变量。为了维持骨量，偶联确保骨形成遵循再吸收。糖尿病可能通过抑制由于糖尿病损害的骨形成引起的偶联来增加牙槽骨丢失。因此，我们将集中在一个以前未报道的方面，即糖尿病干扰新牙槽骨的形成后，骨吸收的插曲。提出的研究的目的是调查一个假设，即糖尿病通过增强TNF-D的产生增加细胞凋亡，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中的解偶联是否是由于TNF-D水平升高所致。这些研究将使用TNF特异性抑制剂依那西普通过腹腔注射来研究TNF-Q的作用。目的2将确定糖尿病增强的细胞凋亡是否代表牙周组织中骨形成和再吸收解偶联的功能重要机制。这些研究将使用腹膜内注射半胱天冬酶抑制剂来阻断大鼠结扎模型中牙周骨吸收事件后骨形成期间的细胞凋亡。目的3研究TNF是否在糖尿病促进成纤维细胞凋亡、糖尿病改变基因表达和基质金属蛋白酶活性中起关键作用。这些研究将使用目标1中描述的大鼠模型和TNF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.