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

描述（由申请人提供）：本项目中拟定的研究目标是确定主动脉瓣疾病（AoVD）的分子机制和开发早期药物治疗的潜在治疗靶点，以阻止AoVD进展并防止手术需求。AoVD影响美国2%的人口。在老年人中，AoVD的患病率增加至10%以上。1 AoV置换手术是重度AoVD最推荐的治疗选择。置换瓣膜与并发症有关。迄今为止，尚无已证实可预防或延迟人类AoVD进展的药物治疗选择。在初步研究中，C 0X 2（环氧合酶2/前列腺素-内过氧化物合酶2）表达在人类患病AoV组织以及来自AoVD小鼠模型的AoV组织中增加。尽管COX 2传统上与炎症过程相关，但它在成骨细胞分化和软骨内骨修复中也起着关键作用。COX 2-/-小鼠具有延迟的骨折愈合和成骨细胞生成缺陷。在骨中，COX 2催化前列腺素E2合成的第一个关键步骤，前列腺素E2通过EP 2受体发出信号使p-38 MAPK磷酸化，随后激活新骨形成所需的成骨途径。为了验证COX 2表达增加介导主动脉瓣间质细胞（VIC）成骨样分化，导致致病性AoV钙化的假设，提出了三个具体目标。(1)确定COX 2在主动脉VIC中的表达是否与成骨基因表达谱的诱导一致。(2)确定COX 2表达是否是通过EP 2/p-p38 MAPK途径促进小鼠VIC成骨分化所必需和充分的。(3)确定COX 2抑制是否可预防体内AoVD钙化的发生并阻止其进展。拟议的研究将确定COX 2是否是病理性AoVD钙化过程所必需的，以及COX 2的抑制是否可以预防或阻止AoV钙化的进展。了解AoV钙化的分子基础将提供对AoVD进展的深入了解，并将确定潜在的药理学治疗靶点，这可能对AoVD的无创治疗具有未来的临床意义。

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.