Knockdown of Interleukin-1Beta Signaling in Osteoarthritis

描述（由申请人提供）：OA是一种与关节退行性变引起的疼痛和功能障碍相关的衰弱性疾病。目前还没有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。阐明OA中关键分子介质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。该提案的中心目标是产生白细胞介素-1 β介导的信号传导的特异性局部减少，以确定这种信号传导在Dunkin Hartley（DH）豚鼠膝关节中自发性骨关节炎（OA）进展中的作用。将检查两种方法以减少IL-1 β介导的信号传导。首先，RNA干扰（RNAi）将用于靶向和降低IL-1 β介导的信号传导所必需的三种因子的表达：（1）IL-1 β;（2）I型IL-1受体;和（3）IL-1 β转化酶。第二，将使用IL-1 R1的可溶性竞争性拮抗剂，白细胞介素-1受体拮抗剂，以降低可溶性IL-1 β的有效浓度。两种方法都将利用自身互补的腺相关病毒血清型5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.