Role of fluid flow on Chlamydia pneumoniae-exacerbated atherosclerosis

描述(申请人提供)：全身性细菌感染引起炎症反应，可导致急性或慢性并发症。我们目前解决这个问题的方法在很大程度上局限于静态系统，尽管现在已经很好地确定了血流动力学可以严重影响细胞反应。这种相互作用的一个明显证据是，动脉粥样硬化斑块几乎总是出现在受干扰的流场区域，如动脉弯曲点或分支点。有趣的是，来自体外实验、血清流行病学、组织病理学、动物模型和有限的临床干预研究的多条证据表明，由一种常见的细胞内呼吸道病原体肺炎衣原体引起的感染极有可能是动脉粥样硬化的危险因素。然而，人们对其机制知之甚少。因此，在细胞和分子水平上了解肺炎衣原体感染与血流之间的复杂相互作用，对于探索预防或治疗心血管疾病的抗感染干预方案具有重要意义。我们假设流体切应力调节肺炎衣原体感染引起的动脉粥样硬化的风险。我们将使用系统生物工程方法来验证我们的假设，其定义如下：(1)评估肺炎衣原体感染和剪应力对单核细胞的生化影响；(2)评估肺炎衣原体感染和剪应力对单核细胞的生物物理影响；以及(3)检测肺炎衣原体感染和剪应力对单核细胞在流动条件下与内皮细胞(EC)黏附和迁移的影响。我们的研究应该为流体流动在肺炎衣原体加重动脉粥样硬化的早期阶段发挥关键作用的机制提供洞察力。在更大的背景下，这一建议为我们理解系统性感染和炎症引入了一种新的范式。

DESCRIPTION (provided by applicant): Systemic bacterial infections elicit inflammatory response that can result in acute or chronic complications. Our current approach to this problem has largely been limited from static systems though it is now well established that the dynamics of blood flow can seriously influence cellular response. A clear demonstration of such an interaction is that atherosclerotic plaques are almost invariably found in regions of disturbed flow fields such as arterial bends or branch points. Of interest, multiple lines of evidence from in vitro experimental, seroepidemiological, histopathological, animal models and limited clinical interventional studies suggest that infection due to a common intracellular respiratory pathogen, Chlamydia pneumoniae is a highly likely risk factor for atherosclerosis. However, the mechanism is poorly understood. Thus, understanding the complex interaction between C. pneumoniae infection and blood flow at cellular and molecular levels is important in exploring options for anti-infective intervention in the prevention or treatment of cardiovascular diseases. We hypothesize that fluid shear stress modulates the risk of atherosclerosis due to C. pneumoniae infection. We will use a systems bioengineering approach to test our hypothesis as defined by the following three specific aims: (1) Evaluate the biochemical effects of C. pneumoniae infection and shear stress on monocytes; (2) Evaluate the biophysical effects of C. pneumoniae infection and shear stress on monocytes; and (3) Examine the effect of C. pneumoniae infection and shear stress on monocyte adhesion to endothelial cells (EC) and transmigration under flow conditions. Our studies should provide insights into mechanisms by which fluid flow plays a critical role in early stages of C. pneumoniae-exacerbated atherosclerosis. In a larger context, this proposal introduces a new paradigm in our approach to understanding systemic infection and inflammation.