Mechano-biologic Determinants of AAA Disease

描述(由申请人提供)：腹主动脉瘤(AAA)疾病是美国老年人常见的致命健康问题。大量证据表明，静坐状态的存在和由此导致的促炎的主动脉血流动力学状况与AAA疾病的发病机制有关。从高危人类受试者、AAA患者和动物模型的活体成像研究中获得的见解对于实现我们的长期目标至关重要；发现和验证能够降低AAA风险、进展和治疗发病率的物理和药物干预措施。我们有两个具体的目标：首先，我们将确定非卧床受试者、小型早期AAA患者和小鼠模型的静息和运动主动脉状况，以及AAA疾病(脊髓损伤)的高危久坐患者的静息状况。这些研究将检验我们的假设：i)长期减少的血流和剪切力是久坐患者AAA风险增加的原因，ii)运动改善小AAA的血液动力学状况，以及iii)可变流量模型重现临床相关的血液动力学条件范围。其次，我们将跟踪炎症细胞在体内的迁移和基因表达，以响应可变的血流条件。这些实验将确定血流负荷和伴随的剪切力和张力力的增加如何减少巨噬细胞的输送、聚集、促炎基因表达以及祖细胞的定位和分化。为了实现这些目标，我们将使用磁共振(MR)成像和计算机模拟来分析和定义人类和小鼠的主动脉血流动力学状况。血流动力学对巨噬细胞迁移、聚集和调节基因表达的影响将通过生物发光和磁共振细胞成像进行分析。在嵌合小鼠中，循环祖细胞的定位和分化将通过双重染色策略进行检测。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) disease is a common and lethal health problem of older Americans. Substantial evidence links sedentary existence and resulting pro-inflammatory aortic hemodynamic conditions to the pathogenesis of AAA disease. Insights derived from in vivo imaging studies in high risk human subjects, AAA patients and animal models are essential to realizing our LONG TERM OBJECTIVE; the discovery and validation of physical and pharmacological interventions capable of reducing AAA risk, progression and treatment morbidity. We have 2 SPECIFIC AIMS: First, we will define rest and exercise aortic conditions in ambulatory subjects, patients with small, early AAA and murine models, as well as resting conditions in sedentary patients at high risk for AAA disease (spinal cord injury). These studies will test our hypotheses that I) chronically reduced flow and shear account for increased AAA risk in sedentary patients, ii) exercise improves hemodynamic conditions in small AAA, and III) variable flow models reproduce to scale clinically relevant ranges of hemodynamic conditions. Second, we will track inflammatory cell migration and gene expression in vivo in response to variable flow conditions. These experiments will define how flow loading and accompanying increased shear and tensile forces reduce macrophage delivery, accumulation, proinflammatory gene expression and progenitor cell localization and differentiation. To ACHIEVE THESE AIMS, we will analyze and define human and murine aortic hemodynamic conditions using magnetic resonance (MR) imaging and computer simulations. Hemodynamic influences on macrophage migration, accumulation and regulatory gene expression will be assayed via bioluminescence and MR cellular imaging. Circulating progenitor cell localization and differentiation will be examined via dual staining strategies in chimeric mice.