Modeling of Endothelial Cell Adhesion Dynamics Modulated by Experimental Molecular Engineering

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。在实验生物力学研究中，一个常见的问题是难以对工程操纵的功效时程进行大量的测试。提出了一个综合实验和计算的分子生物力学模型，用于增强血管重建中内皮细胞粘附。内皮细胞在保护血管免受血栓形成和动脉粥样硬化方面发挥着关键作用，这与血小板活化和血液凝固有关。血管内皮细胞衬里是预防重建血管内膜增生的有效方法。然而，内皮细胞往往脱离重建的动脉，由于弱的粘附强度，阻碍了内皮细胞衬里的有效性。因此，本研究的主要目标是：（1）通过实验性的分子调控来增强内皮细胞的粘附性，（2）计算整合素受体和配体在分子水平上结合的局部接触结合/解离速率，（3）计算整合素受体和配体对结合的局部接触结合/解离速率。以及（3）在各种血流动力学条件下，通过计算模拟来预测调节的内皮细胞的粘附强度。社会影响和学术价值：血管血栓形成、内膜增生和动脉粥样硬化是影响约50%人口的常见疾病。因此，一个新的调查，导致这些疾病的潜在减少将在科学界以及非科学界产生重大影响。所提出的研究，同时使用动脉重建模型作为一个例子，解决了一个基本的主题：通过调节分子活性，一个潜在的有效的工程方法，不仅为基础科研，而且为治疗病理性疾病，以增强所需的细胞功能。虽然这项调查的重点是在动脉重建的内皮细胞粘附，整合计算方法与细胞功能的实验分子调制的概念可以推广和用于其他病理疾病。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).In experimental biomechanical studies, a common problem is the difficulty of conducting a large number of tests for the efficacy time course of engineering manipulation. An integrated experimental and computational molecular biomechanics model for the enhancement of endothelial cell adhesion in arterial reconstruction is proposed. Endothelial cells play a critical role for protecting blood vessels against thrombosis and atherosclerosis, which is associated with platelet activation and blood coagulation. Endothelial cell lining of arterial constructs is an effective approach for preventing intimal hyperplasia in reconstructed arteries. However, endothelial cells often detach from reconstructed arteries due to weak adhesion strength, hampering the effectiveness of endothelial cell lining. Hence, the research thrusts are: (1) the adhesion of endothelial cells will be enhanced by experimental molecular modulation of selected adhesion regulatory factors; (2) the focal contact association/dissociation rates of the intergrin receptor and ligand pair binding at the molecular level will be computed; and (3) the adhesion strength of modulated endothelial cells will be predicted by computational simulation under various hemodynamic conditions. Societal Impact and Intellectual Merit: Vascular thrombosis, intimal hyperplasia, and atherosclerosis are common disorders affecting about 50% of the human population. Thus, a novel investigation leading to a potential reduction in these disorders will elicit significant impact in the scientific as well as non-scientific communities. The proposed research, while using the arterial reconstruction model as an example, addresses a fundamental topic: enhancing a desired cell function by modulating molecular activities, a potentially effective engineering approach not only for basic scientific research but also for the treatment of pathological disorders. Although this investigation focuses on endothelial cell adhesion in arterial reconstruction, the concept of integrating computational approach with experimental molecular modulation of cell function can be generalized and used for other pathological disorders.