Imaging protease activation in calcific aortic valve disease

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。主动脉瓣狭窄是心脏瓣膜病最常见的原因，钙化性主动脉瓣疾病（CAVD）是主动脉瓣狭窄最常见的原因。CAVD的病理学标志是炎症、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导局灶性炎症，其反过来触发瓣膜间质细胞的成骨转化。基质金属蛋白酶（MMPs）介导基质重塑和周转。健康和钙化的人主动脉瓣的表达谱已经在CAVD中上调的前10个基因中鉴定出几种MMP（包括MMP-12）。单核细胞-巨噬细胞是MMP产生和活化的主要来源，并且MMP表达和活化似乎与CAVD中的炎症密切相关。在这里，我们假设CAVD的标志，炎症和重塑，可以通过靶向MMP激活在体内检测，从而提供了一种非侵入性的成像方法，用于早期检测和跟踪治疗干预的效果。我们的具体目标是验证MMP成像用于检测CAVD中的炎症和重塑，研究MMP靶向SPECT成像用于预测结果和跟踪CAVD中治疗干预的效果，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近红外荧光成像评估主动脉瓣解剖结构、功能和生物学。随后进行主动脉瓣组成和生物学的组织学分析。体内MMP示踪剂摄取将与炎症和瓣膜重塑的标志物相关。将早期CAVD动物随机分配至治疗干预组，并通过连续成像研究主动脉瓣解剖结构、功能和生物学，然后进行组织学分析。治疗干预对示踪剂的影响 将解决摄取和CAVD的问题，并确定早期成像预测个体动物结局的能力。MMP-12基因缺失和MMP-12抑制对CAVD的发展和进展以及MMP-12探针摄取的影响将被解决。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，将讨论CAVD病理生物学方面的问题。因此，该提案有望通过确定MMPs在CAVD中的作用，并提供早期评估治疗疗效的非侵入性工具，促进新治疗措施的开发。 (End摘要）

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)