Molecular Imaging of Vascular Remodeling

描述（由申请人提供）：重塑，定义为血管尺寸和/或组成的持久变化，是许多血管疾病的共同特征，包括动脉粥样硬化、动脉瘤和移植物动脉硬化（GA）。血管平滑肌细胞（VSMC）增殖、迁移和基质支架重组导致新生内膜增生和几何重构。炎症在其发病机制中起重要作用。在这里，我们试图建立一个功能的意义？3整合素和基质金属蛋白酶（MMP）活化与新生内膜增生和几何重构的关系。我们假设这种功能意义在不同形式的血管重塑中是有效的和类似的，即小鼠颈动脉丝损伤、GA和动脉瘤。我们的具体目标是：1）调查的程度？3整合素和MMP的激活及其在VSMC和单核-巨噬细胞表型调节中的相互依赖性，2）建立整合素和MMP的功能意义？3）和MMP激活作为机械损伤诱导的血管重塑，GA和动脉瘤的共同介质，和3）评估？3和MMP成像用于预测不同形式血管重构的重构程度。a？3整合素和MMP活化将通过免疫染色和放射免疫测定法在分化和增殖的人VSMC以及静息单核细胞和1型和2型极化巨噬细胞中进行评估。相互激活和物理关联的一个？3整合素和MMP在VSMC和单核巨噬细胞中的表达。MMP和a？3的表达和活化及其与几何重塑和内膜增生的相关性将通过免疫染色、蛋白质印迹、酶谱和形态测定来建立。活化MMP和a？3将被确定，并使用特定的抑制剂确认其功能意义。NC 100692，激活了一个？3 -和RP 782，激活MMP靶向血管成像将被验证并用作研究血管重塑的分子机制的实验工具。a？3和MMP激活将通过双示踪剂a？3和纵向研究中MMP靶向成像。这将建立一个功能的重要性？3和MMP活化作为血管重塑的常见介质，并验证它们作为体内成像的靶点。最终，这可以通过早期监测和干预改善血管患者的护理。

DESCRIPTION (provided by applicant): Remodeling, defined as an enduring change in the size and/or composition of blood vessels, is a common feature of many vascular diseases, including atherosclerosis, aneurysm and graft arteriosclerosis (GA). Vascular smooth muscle cell (VSMC) proliferation and migration and matrix scaffold reorganization lead to neointimal hyperplasia and geometrical remodeling. Inflammation plays an important role in the pathogenesis. Here, we seek to establish the functional significance of a?¿3 integrin and materix metalloproteinase (MMP) activation in relation to neointimal hyperplasia and geometrical remodeling. We hypothesize this functional significance is valid and analogous in different forms of vascular remodeling, namely murine carotid wire injury, GA and aneurysm. Our specific aims are to: 1) investigate the extent of a?¿3 integrin and MMP activation and their interdependence in VSMC and monocyte-macrophage phenotypic modulation, 2) establish the functional significance of a?¿3 and MMP activation as common mediators of mechanical injury-induced vascular remodeling, GA and aneurysm, and 3) assess a?¿3 and MMP imaging for predicting the extent of remodeling in different forms of vascular remodeling. a?¿3 integrin and MMP activation will be assessed by immunostaining and radioimmunoassay in differentiated and proliferative human VSMC, as well as resting monocytes and types 1 and 2 polarized macrophages. Reciprocal activation and physical association of a?¿3 integrin and MMP in VSMC and monocytemacrophages will be addressed. MMP and a?¿3 expression and activation and their correlation with geometrical remodeling and intimal hyperplasia will be established by immunostaining, Western blotting, zymography, and morphometry. Cellular sources of activated MMP and a?¿3 will be identified, and their functional significance confirmed using specific inhibitors. NC100692, activated a?¿3 - and RP782, activated MMP-targeted vascular imaging will be validated and utilized as experimental tools to study the molecular mechanisms of vascular remodeling. a?¿3 and MMP activation will be assessed by dual tracer a?¿3 and MMP-targeted imaging in longitudinal studies. This will establish the functional significance of a?¿3 and MMP activation as common mediators of vascular remodeling, and validate them as targets for in vivo imaging. Ultimately, this can improve the care of vascular patients through early monitoring and intervention.