Imaging protease activation in calcific aortic valve disease

钙化性主动脉瓣疾病中蛋白酶激活的成像

• 批准号: 9086412
• 负责人: MEHRAN M SADEGHI
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086412
• 关键词: Address; Anatomy; Animal Model; Animals; Aortic Valve Stenosis; Apolipoprotein E; Basic Science; Biology; Calcinosis; Cardiology; Cells; Cessation of life; Clinical; Deposition; Detection; Development; Doxycycline; Early Diagnosis; Echocardiography; Epitopes; Extracellular Matrix; Family; Fatty acid glycerol esters; Fibrosis; Future; Gene Deletion; Genes; Goals; Heart Valve Diseases; High Fat Diet; Human; Hyperlipidemia; Image; Individual; Inflammation; Inflammatory; Instruction; Label; Lead; Link; Lipids; Matrix Metalloproteinases; Measures; Mechanical Stress; Mediating; Mediator of activation protein; Metalloproteases; Modality; Molecular Profiling; Mus; Nuclear; Outcome; Pathogenesis; Peptide Hydrolases; Photons; Play; Production; Randomized; Risk Factors; Role; Source; Specificity; Staging; Therapeutic Intervention; Tracer; Translations; Treatment Efficacy; Work; X-Ray Computed Tomography; abstracting; aortic valve; aortic valve disorder; base; calcification; cell transformation; clinical application; design; feeding; fluorescence imaging; high risk; imaging modality; in vivo; inflammatory marker; inhibitor/antagonist; interstitial; interstitial cell; macrophage; member; microSPECT; molecular imaging; monocyte; mouse model; non-invasive imaging; novel; novel therapeutics; particle; research study; response; single photon emission computed tomography; targeted imaging; tool; uptake; western diet

DESCRIPTION (provided by applicant): Valvular heart disease is responsible for ~23,000 deaths per year in the US. Aortic stenosis is the most common cause of valvular heart disease and calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Pathological hallmarks of CAVD are Inflammation, extracellular matrix remodeling (including fibrosis) and calcification. Mechanical stress, atherosclerotic risk factors, deposition of lipid particles, and other factors induce focal inflammation which in turn triggers osteoblastic transformation of valvular interstitial cells. Matix metalloproteinases (MMPs) mediate matrix remodeling and turnover. Expression profiling of healthy and calcific human aortic valve has identified several MMPs (including MMP- 12) amongst the top 10 genes upregulated in CAVD. Monocyte-macrophages are major sources of MMP production and activation and MMP expression and activation appear to be closely linked to inflammation in CAVD. Here, we hypothesize that hallmarks of CAVD, inflammation and remodeling, can be detected by targeting MMP activation in vivo, thus providing a non-invasive imaging approach for early detection and tracking the effect of therapeutic intervention. Our specific aims are to validate MMP imaging for detection of inflammation and remodeling in CAVD, investigate MMP-targeted SPECT imaging for predicting outcome and tracking the effect of therapeutic interventions in CAVD, and evaluate MMP-12 as target for molecular imaging of early CAVD. Using two complementary murine models of CAVD we will evaluate aortic valve anatomy, function and biology by echocardiography, CT and MMP-targeted microSPECT or MMP-12 near infrared fluorescent imaging. This will be followed by histological analysis of aortic valve composition and biology. MMP tracer uptake in vivo will be correlated with markers of inflammation and valvular remodeling. Animals with early CAVD will be randomly assigned to therapeutic interventions and aortic valve anatomy, function and biology will be investigated by serial imaging followed by histological analysis. The effect of therapeutic interventions on tracer uptake and CAVD will be addressed and the ability of early imaging to predict outcome in individual animals will be determined. The effect of MMP-12 gene deletion and MMP-12 inhibition on the development and progression of CAVD and MMP-12 probe uptake will be addressed. In line with the main purpose of the RFA, the proposed experiments are primarily designed to validate MMP-targeted imaging for early diagnosis of CAVD. In parallel, aspects of CAVD pathobiology will be addressed. As such, the proposal is expected to facilitate the development of novel therapeutic measures by establishing the role of MMPs in CAVD and providing non-invasive tools for early assessment of treatment efficacy. (End of Abstract)

描述（由申请人提供）： 在美国，瓣膜性心脏病每年导致约 23,000 人死亡。主动脉瓣狭窄是瓣膜性心脏病的最常见原因，钙化性主动脉瓣疾病（CAVD）是主动脉瓣狭窄的最常见原因。 CAVD 的病理特征是炎症、细胞外基质重塑（包括纤维化）和钙化。机械应力、动脉粥样硬化危险因素、脂质颗粒沉积和其他因素诱发局灶性炎症，进而引发瓣膜间质细胞的成骨细胞转化。 Matix 金属蛋白酶 (MMP) 介导基质重塑和周转。对健康和钙化人主动脉瓣的表达谱分析已确定了 CAVD 中上调的前 10 个基因中的几个 MMP（包括 MMP-12）。单核细胞-巨噬细胞是 MMP 产生和激活的主要来源，MMP 表达和激活似乎与 CAVD 炎症密切相关。在这里，我们假设 CAVD 的标志、炎症和重塑，可以通过靶向体内 MMP 激活来检测，从而为早期检测和跟踪治疗干预的效果提供非侵入性成像方法。我们的具体目标是验证 MMP 成像用于检测 CAVD 炎症和重塑，研究 MMP 靶向 SPECT 成像用于预测结果和跟踪 CAVD 治疗干预的效果，并评估 MMP-12 作为早期 CAVD 分子成像的靶点。使用两种互补的 CAVD 小鼠模型，我们将通过超声心动图、CT 和 MMP 靶向 microSPECT 或 MMP-12 近红外荧光成像来评估主动脉瓣解剖结构、功能和生物学。随后将进行主动脉瓣成分和生物学的组织学分析。体内 MMP 示踪剂的摄取将与炎症和瓣膜重塑的标志物相关。患有早期 CAVD 的动物将被随机分配接受治疗干预，并通过连续成像和随后的组织学分析来研究主动脉瓣解剖、功能和生物学。治疗干预对示踪剂的影响 将解决摄取和 CAVD 问题，并确定早期成像预测个体动物结果的能力。将讨论 MMP-12 基因缺失和 MMP-12 抑制对 CAVD 的发生和进展以及 MMP-12 探针摄取的影响。与 RFA 的主要目的一致，所提出的实验主要旨在验证 MMP 靶向成像用于 CAVD 的早期诊断。同时，还将讨论 CAVD 病理学的各个方面。因此，该提案预计将通过确定 MMP 在 CAVD 中的作用并为早期评估治疗效果提供非侵入性工具来促进新型治疗措施的开发。 （摘要完）

项目成果

Molecular imaging of calcific aortic valve disease.

钙化性主动脉瓣疾病的分子影像。

• DOI: 10.1007/s12350-017-1158-7
• 发表时间: 2018
• 期刊: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
• 作者: Jung,Jae-Joon;Jadbabaie,Farid;Sadeghi,MehranM
• 通讯作者: Sadeghi,MehranM