Knockdown of Interleukin-1Beta Signaling in Osteoarthritis

描述(申请人提供)：骨性关节炎是一种衰弱的疾病，与关节退行性变引起的疼痛和功能障碍有关。目前还没有一种治疗方案能够将受损的软骨恢复到其正常表型或减缓关节破坏的进展。确认关键分子介体在骨性关节炎中的作用及其相互关系将提供重要信息，并有助于确定适当的药物或分子干预措施。这项建议的中心目标是产生一种特定的、局部的IL-1β介导的信号减少，以确定这种信号在Dunkin Hartley(DH)豚鼠膝关节自发性骨关节炎(OA)进展中的作用。将研究两种方法来减少IL-1β介导的信号转导。首先，RNA干扰(RNAi)将被用来靶向和减少IL-1β介导的信号传递所必需的三个因子的表达：(1)IL-1β；(2)I型IL-1受体；(3)IL-1β转换酶。其次，IL-1R1的可溶性竞争性拮抗剂IL-1受体拮抗剂IL-1受体拮抗剂将用于降低可溶性IL-1β的有效浓度。这两种方法都将利用自身互补的腺相关病毒5型载体。

DESCRIPTION (provided by applicant): OA is a debilitating disease associated with pain and dysfunction caused by joint degeneration. There is currently no treatment regimen that is able to restore damaged cartilage to its normal phenotype or slow the progression of joint destruction. Confirming the contributions of the key molecular mediators in OA, as well as their interrelationships, will provide vital information and assist with defining appropriate pharmaceutical or molecular interventions. The central goal of this proposal is to generate a specific, localized reduction of interleukin-1 beta mediated signaling to define the role of such signaling in the progression of spontaneous osteoarthritis (OA) in the knee joints of Dunkin Hartley (DH) guinea pigs. Two methods will be examined to decrease IL-1 beta mediated signaling. First, RNA interference (RNAi) will be used to target and reduce the expression of three factors necessary for IL-1 beta mediated signaling: (1) IL-1beta; (2) type I IL-1 receptor; and (3) IL-1 beta converting enzyme. Second, a soluble competitive antagonist of IL-1 R1, interleukin-1 receptor antagonist, will be employed to reduce the effective concentration of soluble IL-1 beta. Both methods will utilize self-complementary adeno-associated viral serotype 5 vectors.