Wnt-4 inhibits peridontitis by attenuating NF-kB

描述(由申请人提供)：本次竞争性更新的长期目标是通过抑制核因子-kappaB(NF-kB)来开发治疗牙周炎的新疗法。牙周炎是最常见的炎症性疾病，常破坏牙周组织和牙槽骨，导致牙齿失去支撑力。更重要的是，越来越多的证据表明，慢性牙周炎是心血管疾病、口腔癌、糖尿病和其他系统性疾病的重要危险因素。因此，它代表了老龄化人口中一个重要的公众关切。多种促炎分子，包括肿瘤坏死因子(TNF)、白介素1(IL-1)、IL-6、IL-8、细胞间黏附分子-1、环氧合酶-2(COX-2)、基质金属蛋白酶(MMP)-1和基质金属蛋白酶-9，与牙周炎和骨丢失有关。我们团队和其他人的基础科学发现已经证明，核因子-kB是一种控制促炎分子表达的主要转录因子。利用基因组学和生物信息学的方法，我们发现大多数牙周病原体诱导的早期反应基因都依赖于核因子-kB。最近，我们还发现，核因子-kB的激活介导了骨形成与骨吸收的解偶联，为牙周炎修复的受损提供了新的解释。因此，从开发牙周炎新疗法的角度来看，靶向核因子-kB可能比单一细胞因子更有效。在筛选抑制核因子-kB的新分子时，我们出人意料地发现，WNT-4蛋白在体外和体内都能抑制牙周炎症并促进修复。基于我们的初步研究，在这一竞争更新中，我们假设WNT-4通过减弱NF-kB的激活来预防牙周炎和骨丢失。为了检验我们的假设，本文提出了三个具体目标。目的1确定WNT-4是否通过抑制体内核因子-kB的活化来预防牙周炎和牙槽骨丢失。目的2探讨重组WNT-4蛋白在体内能否通过抑制核因子-kB的活化来抑制牙周炎的进展，维持牙槽骨的形成。目的3探讨WNT-4抑制炎症介质诱导的核因子-kB活化的分子机制。本研究结果将为以核因子-kB为靶点预防和治疗牙周炎提供重要的理论依据，并为IKK/核因子-kB抑制剂的临床试验奠定重要基础。 公共卫生相关性：牙周炎是最常见的炎症性疾病，经常破坏牙槽骨和牙周组织，导致牙齿失去支撑。据估计，超过80%的30岁以上的成年人有牙周骨丢失，50%的60岁以上的成年人由于严重的骨丢失而患有晚期牙周炎和几颗松动的牙齿。更重要的是，越来越多的证据表明，慢性牙周炎是心血管疾病、口腔癌、糖尿病和其他系统性疾病的重要危险因素。因此，它代表了老龄化人口中一个重要的公众关切。在这项应用中，我们将测试WNT-4蛋白可以通过减弱体外和体内的炎症反应来抑制牙周病和防止组织破坏。这项研究的发现将对开发治疗牙周病或其他炎症性疾病的新生物策略具有重要意义。

DESCRIPTION (provided by applicant): The long-term objectives of this competing renewal are to develop novel therapeutics for periodontitis by inhibiting nuclear factor-kappa B (NF-kB). Periodontitis is the most common inflammatory disease and often destroys periodontal tissues and alveolar bone, resulting in loss of tooth support. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. Multiple pro-inflammatory molecules, including tumor necrosis factor (TNF), interleulin-1 (IL-1), IL-6, IL-8, intercellular adhesion molecule-1, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-1, and MMP-9, are associated with periodontal inflammation and bone loss. Basic science discoveries from our group and others have demonstrated that NF-kB is a master transcription factor that controls the expression of pro-inflammatory molecules. Using genomic and bioinformatic approaches, we have found that the majority of early-response genes induced by periodontal pathogens are dependent on NF-kB. Recently, we also discovered that the activation of NF-kB mediates the uncoupling of bone formation from bone resorption, providing a novel explanation for the compromised repair in periodontitis. Therefore, from the standpoint of developing novel therapeutics for periodontitis, targeting NF-kB may be more effective than single cytokines. In screening for novel molecules that inhibits NF-kB, unexpectedly, we discovered that Wnt-4 proteins inhibited periodontal inflammation and promoted repair in vitro and in vivo. Based on our preliminary studies, in this competing renewal, we hypothesize that Wnt-4 prevents periodontal inflammation and bone loss by attenuating NF-kB activation. Three specific aims are proposed to test our hypothesis. Aim 1 is to determine whether Wnt-4 prevents periodontal inflammation and alveolar bone loss by attenuating NF-kB activation in vivo. Aim 2 is to explore whether recombinant Wnt-4 proteins can inhibit the progression of periodontitis and maintains alveolar bone formation by attenuating NF-kB activation in vivo. Aim 3 is to explore the molecular mechanisms by which Wnt-4 suppresses NF-kB activation induced by inflammatory mediators. The results should provide an important proof-of-principal in the prevention and treatment of periodontitis by targeting NF-kB, and lay the important foundation for the clinical trials involving the IKK/NF-kB inhibitors. PUBLIC HEALTH RELEVANCE: Periodontitis is the most common inflammatory disease and often destroys alveolar bone and periodontal tissues, resulting in loss of tooth support. It is estimated that over 80% of adults over age 30 have periodontal bone loss and 50% of adults over age 60 have advanced periodontitis with several loose teeth due to severe bone loss. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. In this application, we will tet Wnt-4 proteins can inhibit gum diseases and prevent tissue destruction by attenuating inflammatory responses in vitro and in vivo. The findings from this study will have important implications in developing novel biological strategies for treating gum diseases or other inflammatory diseases.