Imaging protease activation in calcific aortic valve disease

描述(由申请人提供)： 在美国，瓣膜心脏病每年造成约23,000人死亡。主动脉瓣狭窄是心脏瓣膜病最常见的病因，钙化性主动脉瓣病(CAVD)是主动脉瓣狭窄最常见的原因。CAVD的病理特征是炎症、细胞外基质重构(包括纤维化)和钙化。机械应力、动脉粥样硬化危险因素、脂质颗粒沉积等因素导致局部炎症，进而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确定了几个MMPs(包括MMP12)在CAVD中上调的前10个基因中。单核巨噬细胞是MMPs产生和激活的主要来源，MMPs的表达和激活似乎与CAVD的炎症密切相关。在这里，我们假设CAVD的特征，炎症和重塑，可以通过在体内靶向激活MMP来检测，从而为早期发现和追踪治疗干预的效果提供了一种非侵入性的成像方法。我们的具体目标是验证基质金属蛋白酶显像检测CAVD的炎症和重塑，研究靶向基质金属蛋白酶SPECT显像预测预后和追踪治疗干预措施的效果，并评价基质金属蛋白酶-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MMP12近红外荧光成像来评估主动脉瓣的解剖、功能和生物学。随后将对主动脉瓣成分和生物学进行组织学分析。体内的基质金属蛋白酶示踪剂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到治疗干预组，并将通过系列成像和组织学分析来研究主动脉瓣的解剖、功能和生物学。治疗性干预对示踪剂的影响 摄取和CAVD将被解决，早期成像预测单个动物结果的能力将被确定。我们将讨论基质金属蛋白酶-12基因缺失和基质金属蛋白酶-12抑制对CAVD的发生和发展的影响以及基质金属蛋白酶-12探针摄取。根据RFA的主要目的，建议的实验主要是为了验证基质金属蛋白酶靶向成像在CAVD早期诊断中的有效性。同时，还将讨论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中的作用并为早期评估治疗效果提供非侵入性工具，促进新的治疗措施的开发。 (摘要结束)

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)