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

COX2 在钙化性主动脉瓣疾病进展中的作用

• 批准号: 8448393
• 负责人: Elaine Emily Wirrig
• 金额: $ 5.39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448393
• 关键词: Adenoviruses; Adult; Affect; Agonist; Alkaline Phosphatase; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Bone Regeneration; Cell Culture Techniques; Clinical; Commit; Coxibs; Defect; Development; Dinoprostone; Disease Progression; Enzymes; Fracture Healing; Future; Gene Expression; Gene Expression Profile; Goals; Human; Inflammatory; Injection of therapeutic agent; MAP Kinase Gene; MAPK14 gene; Mediating; Medical; Microarray Analysis; Modeling; Molecular; Mus; NS-398; Onset of illness; Operative Surgical Procedures; Osteocalcin; Osteogenesis; Outcome; PTGS2 gene; Pain; Pathologic; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Play; Population; Premature aging syndrome; Prevalence; Prevention; Process; Prostaglandin Receptor; Prostaglandins; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Specimen; Staging; Testing; Tissues; United States; Wild Type Mouse; aged; aortic valve; aortic valve disorder; aortic valve replacement; base; bone; bone mass; calcification; cyclooxygenase 2; gene induction; in vivo; inhibitor/antagonist; insight; interstitial cell; mouse model; new therapeutic target; osteoblast differentiation; osteogenic; p38 MAPK Signaling Pathway; prevent; prostaglandin EP2 receptor; protein expression; research study; therapeutic target; valve replacement

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.

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 (AoVD) 的分子机制和开发早期医疗的潜在治疗靶点，以阻止 AoVD 进展并避免手术需要。 AoVD 影响 2% 的美国人口。在老年人中，AoVD 的患病率增至 10% 以上。1 AoV 替代手术是严重 AoVD 最推荐的治疗选择。更换瓣膜会带来并发症。迄今为止，尚无药物治疗方案被证明可以预防或延缓人类 AoVD 的进展。在初步研究中，COX2（环氧合酶 2/前列腺素内过氧化物合酶 2）在人类患病 AoV 组织以及 AoVD 小鼠模型的 AoV 组织中表达均增加。尽管 COX2 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发挥着关键作用。 COX2-/- 小鼠出现骨折愈合延迟和成骨细胞生成缺陷。在骨骼中，COX2 催化前列腺素 E2 合成的第一个关键步骤，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需的成骨途径。为了检验 COX2 表达增加介导主动脉瓣膜间质细胞 (VIC) 的成骨样分化，导致致病性 AoV 钙化的假设，提出了三个具体目标。 (1) 确定主动脉 VIC 中 COX2 的表达是否与成骨基因表达谱的诱导一致。 (2)确定COX2表达是否是通过EP2/p-p38 MAPK途径促进小鼠VIC成骨分化所必需和充分的。 (3) 确定 COX2 抑制是否可以阻止体内现有 AoVD 钙化的发生并阻止其进展。拟议的研究将确定 COX2 是否是病理性 AoVD 钙化过程所必需的，以及抑制 COX2 是否可以预防或阻止 AoV 钙化的进展。了解 AoV 钙化的分子基础将有助于深入了解 AoVD 的进展，并确定潜在的药理学治疗靶点，这可能对 AoVD 的非侵入性治疗具有未来的临床意义。