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作的功效时间过程进行大量的测试。本文提出了动脉重建过程中内皮细胞粘附增强的综合实验和计算分子生物力学模型。内皮细胞在保护血管免受血栓形成和动脉粥样硬化方面起着至关重要的作用，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动脉内膜增生的有效途径。然而，由于血管内皮细胞黏附强度较弱，内皮细胞经常脱离重建动脉，影响了内皮细胞内膜的作用。因此，研究的重点是：(1)内皮细胞的粘附将通过选择粘附调节因子的实验分子调节而增强；(2)计算分子水平上间素受体和配体对结合的焦点接触结合/解离率；(3)通过计算模拟预测不同血流动力学条件下调节后内皮细胞的粘附强度。社会影响和智力价值：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，一项导致这些疾病潜在减少的新研究将在科学界和非科学界引起重大影响。该研究以动脉重建模型为例，提出了一个基本的主题：通过调节分子活动来增强所需的细胞功能，这是一种潜在的有效的工程方法，不仅适用于基础科学研究，也适用于病理疾病的治疗。虽然本研究的重点是动脉重建中的内皮细胞粘附，但将计算方法与细胞功能的实验分子调节相结合的概念可以推广并用于其他病理疾病。

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.