Signature Protein Profiles to Identify Disease Progression and Therapeutic Modification in Murine and Human Models of Aortic Abdominal Aneurysms

腹主动脉瘤（AAA）被定义为肾下主动脉的病理性扩张，通常伴有明显的叠加动脉粥样硬化、炎症和血栓形成。虽然AAAs很常见，而且往往是致命的，但其形成的潜在机制尚不清楚。同样重要的是，没有足够的方法来快速分层动脉瘤发展、进展或最终破裂的风险。我的假设是，AAAs产生独特的蛋白质特征，包括炎症、细胞凋亡、细胞外基质分解和血栓形成等方面。因此，通过使用定制蛋白微阵列对血清进行检测，我预计我们将识别出血管衍生蛋白的独特模式，这些蛋白将作为AAA发展的敏感和特异性标记物。AAAs在疾病的自然过程中产生和分泌特定的蛋白质，这些蛋白质可以在血清中被检测到。这些蛋白的混合表达模式将比任何单一蛋白对AAA更敏感和特异性。此外，可以监测蛋白质谱以预测动脉瘤扩张，以及对新型治疗方法的反应，如基质金属蛋白酶抑制剂、胶原合成激活剂和他汀类药物的抗炎作用。我们建议在斯坦福大学之前的工作基础上建立一个抗体微阵列，分析与动脉粥样硬化相关的炎症蛋白，并补充通过来自人类AAAs的组织转录分析鉴定的蛋白质以及预测小鼠模型。

An abdominal aortic aneurysm (AAA) is defined as a pathologic dilatation of the infrarenal aorta that is often accompanied by significant superimposed atherosclerosis, inflammation and thrombosis. While AAAs are common and often lethal, the underlying mechanisms of formation are not well understood. Equally important, there are not adequate means to rapidly stratify risk of aneurysm development, progression, or ultimately, rupture. My hypothesis is that AAAs produce unique signature profiles of proteins that include aspects of inflammation, apoptosis, extracellular matrix breakdown and thrombosis. Thus, by interrogation of serum with custom protein microarrays, I anticipate that we will identify unique patterns of vascular-derived proteins that will serve as sensitive and specific markers of AAA development. AAAs produce and secrete specific proteins during the natural course of disease that can be interrogated in serum. The expression pattern of a mix of these proteins will be more sensitive and specific for AAA than any single protein. In addition, protein profiles can be monitored for prediction of aneurysm expansion as well as response to new therapeutical approaches like matrix-metalloproteinase-inhibitors, activators of collagen synthesis, and anti-inflammatory effects of statins. We propose to build an antibody microarray based on the previous work done at Stanford University profiling inflammatory proteins associated with atherosclerosis and supplementing this list with proteins identified by transcriptional profiling of tissue derived from human AAAs as well as predictive murine models.