The Role of COX2 in the Progression of Calcific Aortic Valve Disease

描述（由申请人提供）：本项目提出的研究目标是确定主动脉瓣疾病（aortic valve disease, AoVD）的分子机制和潜在的治疗靶点，以发展早期医学治疗，阻止AoVD的进展，避免手术的需要。美国2%的人口患有心血管疾病。在老年人中，avvd的患病率增加到10%以上AoV置换手术是重度AoVD最推荐的治疗选择。瓣膜置换术伴有并发症。迄今为止，还没有药物治疗方案被证明可以预防或延缓人类avvd的进展。在初步研究中，COX2（环氧化酶2/前列腺素-内过氧化物合酶2）在人AoV病变组织和AoVD小鼠模型AoV组织中的表达均升高。虽然COX2传统上与炎症过程有关，但它在成骨细胞分化和软骨内骨修复中也起着关键作用。COX2-/-小鼠骨折愈合延迟，成骨细胞发生缺陷。在骨骼中，COX2催化前列腺素E2合成的第一步，前列腺素E2通过EP2受体发出信号磷酸化p-38 MAPK，随后激活新骨形成所必需的成骨途径。为了验证COX2表达增加介导主动脉瓣间质细胞（VICs）的成骨样分化，导致致病性主动脉瓣间质钙化的假设，提出了三个具体目标。(1)确定COX2在主动脉VICs中的表达是否与成骨基因表达谱的诱导一致。(2)确定COX2表达是否通过EP2/p-p38 MAPK通路促进小鼠vic成骨分化的必要和充分条件。(3)确定COX2抑制是否能阻止体内存在的avvd钙化的发生和停止其进展。拟议的研究将确定COX2在病理性AoV钙化过程中是否必要，以及COX2的抑制是否可以防止或阻止AoV钙化的进展。了解AoV钙化的分子基础将有助于深入了解AoVD的进展，并将确定潜在的药物治疗靶点，这可能对未来AoVD的无创治疗具有临床意义。

DESCRIPTION (provided by applicant): The goal of the research proposed in this project is to identify the molecular mechanisms underlying aortic valve disease (AoVD) and potential therapeutic targets for the development of early medical treatment to halt AoVD progression and prevent the need for surgery. AoVD affects 2% of the United States population. In the aged, the prevalence of AoVD increases to greater than 10%.1 AoV replacement surgery is the most recommended treatment option for severe AoVD. Replacement valves are associated with complications. To date, there are no pharmacological treatment options that have been proven to prevent or delay the progression of AoVD in humans. In preliminary studies, COX2 (cyclooxygenase 2/prostaglandin- endoperoxide synthase 2) expression is increased in both human diseased AoV tissues as well as in AoV tissues from a mouse model of AoVD. Although COX2 is traditionally associated with the inflammatory process, it also plays a critical role in osteoblast differentiation and endochondral bone repair. COX2-/- mice have delayed fracture healing and defects in osteoblastogenesis. In bone, COX2 catalyzes the first committed step in the synthesis of prostaglandin E2, which signals via the EP2 receptor to phosphorylate p-38 MAPK, which subsequently activates an osteogenic pathway necessary for new bone formation. To test the hypothesis that increased expression of COX2 mediates an osteogenic-like differentiation of the aortic valvular interstitial cells (VICs), leading to pathogenic AoV calcification, three specific aims are proposed. (1) Determine if COX2 expression in aortic VICs is coincident with the induction of an osteogenic gene expression profile. (2) Determine if COX2 expression is necessary and sufficient to promote osteogenic differentiation in mouse VICs via the EP2/p-p38 MAPK pathway. (3) Determine if COX2 inhibition prevents the onset of, and halts the progression of existing, AoVD calcification in vivo. The proposed studies will determine whether COX2 is necessary for the process of pathologic AoVD calcification and if inhibition of COX2 prevents, or halts the progression of, AoV calcification. Understanding the molecular basis of AoV calcification will provide insight into AoVD progression and will identify potential pharmacological therapeutic targets, which may have future clinical implications in non-invasive treatment of AoVD.