Suppression of AVIC inflammosteogenesis for prevention of CAVD progression

抑制 AVIC 炎症生成以预防 CAVD 进展

• 批准号: 10220113
• 负责人: XIANZHONG MENG
• 金额: $ 51.73万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220113
• 关键词: ADAMTS; Address; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Aortic Valve Stenosis; Applications Grants; Attenuated; BMP2 gene; Cardiovascular Diseases; Cells; Collagen; Development; Disease; Disease Progression; Down-Regulation; Elderly; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Funding; Goals; Heart failure; Human; Immunologic Receptors; Indolent; Innate Immune Response; Intervention; Knowledge; Lesion; Mediating; Mediator of activation protein; Molecular; Myofibroblast; NF-kappa B; Natural Immunity; Patients; Pattern; Peptide Hydrolases; Pharmacology; Phenotype; Pilot Projects; Play; Prevention; Proteins; Role; Signal Pathway; Signal Transduction; TLR2 gene; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Work; anti aging; aortic valve; aortic valve disorder; aortic valve replacement; base; calcification; clinically significant; cytokine; disease phenotype; insight; interstitial cell; klotho protein; macrophage; matrilin 2; monocyte; novel; osteogenic; oxidized low density lipoprotein; paracrine; repaired; therapeutic target; transcription factor

Project Summary Calcific aortic valve disease (CAVD) is common in the elderly. CAVD progression to significant aortic stenosis occurs over years in most patients. This indolent course affords the opportunity for therapeutic intervention to halt the disease progression at an early stage. However, limited knowledge of mechanisms underlying CAVD progression impedes the development of effective pharmacological therapies. In the current funding period, our extensive studies have identified signaling mechanisms mediated by innate immune receptors, particularly TLR2 and TLR4, as regulators of the fibrogenic and osteogenic activities in human aortic valve interstitial cells (AVICs). We also discovered that oxidized low-density lipoprotein (oxLDL) and extracellular matrix (ECM) protein matrilin 2 function as damage-associated molecular patterns (DAMPs) in human AVICs, prompting differential cell activation with elevated fibrogenic and osteogenic activities. In addition we observed that human monocytes activated by TLR2 up-regulate AVIC expression of pro-fibrogenic and pro-osteogenic mediators via a paracrine mechanism. Planned studies in this renewal application will test the central hypothesis that distinct molecular mechanisms triggered by AVIC innate immune response elevate cellular and valvular fibrogenic and osteogenic activities through induction of cell activation and/or myofibroblastic transition. We further hypothesize that down- regulation of AVIC innate immune response has therapeutic potential to suppress valvular fibrosis and calcification. These hypotheses are based on our recent observation that oxLDL elevates AVIC fibrogenic and osteogenic activities through a myofibroblast transition-independent mechanism, whereas soluble matrilin 2 elevates these activities in human AVICs through inducing myofibroblastic transition. Moreover, we discovered that human AVICs express anti-aging protein Klotho. This anti-aging protein is capable of modulating AVIC innate immune response. Interestingly, Klotho levels are much lower in aortic valve tissues and AVICs from patients with CAVD, and Klotho insufficiency exacerbates valvular fibrogenic and osteogenic activities. This grant application will address: (1) the mechanisms underlying AVIC fibrogenic and osteogenic activities, (2) the mechanism by which Klotho insufficiency exacerbates AVIC fibrogenic and osteogenic activities, (3) anti- inflammatory approaches to up-regulate Klotho expression in aortic valve and (4) the therapeutic potential of Klotho to alleviate valvular fibrosis and calcification. This proposed work will provide mechanistic insights into the pathobiology of CAVD progression and identify therapeutic targets for pharmacological intervention to halt CAVD progression.

项目摘要 钙化性主动脉瓣疾病（CAVD）在老年人中很常见。CAVD进展为显著主动脉瓣狭窄 在大多数患者中持续多年。这种惰性过程提供了治疗干预的机会， 在早期阶段阻止疾病的发展。然而，对CAVD潜在机制的了解有限， 进展阻碍了有效药物治疗的发展。在目前的融资期内， 广泛的研究已经确定了由先天免疫受体，特别是TLR 2介导的信号传导机制 和TLR 4作为人主动脉瓣间质细胞（AVIC）中纤维形成和成骨活性的调节剂。 我们还发现氧化低密度脂蛋白（oxLDL）和细胞外基质（ECM）蛋白基质蛋白（matrilin） 2在人类AVIC中作为损伤相关分子模式（DAMP）发挥作用， 活化，具有升高的纤维生成和成骨活性。此外，我们还观察到， 由TLR 2激活，通过旁分泌上调促纤维化和促成骨介质的AVIC表达 机制本更新申请中计划的研究将测试中心假设，即不同的分子 由AVIC先天免疫应答触发的机制提高了细胞和瓣膜的纤维化和成骨 通过诱导细胞活化和/或肌纤维母细胞转化来产生活性。我们进一步假设- AVIC先天免疫应答的调节具有抑制瓣膜纤维化的治疗潜力， 钙化这些假设是基于我们最近的观察，即oxLDL升高了AVIC纤维化， 成骨活性通过肌成纤维细胞转化独立的机制，而可溶性matrilin 2 通过诱导成肌纤维细胞转化提高人AVIC中的这些活性。此外，我们发现， 人类AVIC表达抗衰老蛋白Klotho。这种抗衰老蛋白能够调节AVIC 先天免疫反应有趣的是，Klotho水平在主动脉瓣组织和AVIC中低得多， 患有CAVD的患者，Klotho功能不全加剧了瓣膜纤维化和成骨活性。这笔赠款 应用将解决：（1）AVIC纤维化和成骨活性的机制，（2） Klotho功能不全加剧AVIC纤维化和成骨活性的机制，（3）抗- 上调主动脉瓣Klotho表达的炎症途径和（4） Klotho可缓解瓣膜纤维化和钙化。这项拟议的工作将提供机械的见解， CAVD进展的病理生物学并确定药物干预的治疗靶点以阻止 CAVD进展。