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)的分子机制和潜在的治疗目标，以开发早期药物治疗来阻止AoVD的进展并防止手术的需要。AoVD影响2%的美国人口。在老年人中，AoVD的患病率增加到10%以上。1 AOV置换术是重度AoVD最推荐的治疗选择。替换瓣膜与并发症有关。到目前为止，还没有被证明可以预防或延缓人类AoVD进展的药物治疗方案。在初步研究中，COX2(环氧合酶2/前列腺素-过氧化物合成酶2)在人类AOV病变组织以及AOVD小鼠模型的AOV组织中的表达都增加。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发挥着关键作用。COX2-/-小鼠骨折愈合延迟，成骨细胞形成缺陷。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，使p-38MAPK磷酸化，从而激活新骨形成所需的成骨途径。为了验证COX2表达增加介导主动脉瓣间质细胞(VICs)向成骨样分化，从而导致AOV钙化的假说，提出了三个特定的目标。(1)确定COX2在主动脉VICS中的表达是否符合成骨基因表达谱的诱导。(2)确定COX2的表达是否通过EP2/p-p38MAPK通路促进小鼠VICs的成骨分化。(3)确定抑制COX2是否可以阻止体内现存的AoVD钙化的发生和进展。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是否可以阻止或阻止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AoVD的非侵入性治疗具有未来的临床意义。