Fast Drug Screening via Mechanics of Tissue Constructs

描述（由申请人提供）：含有大量潜在可用作药物的化合物的文库的可用性提出了筛选这些化合物的药物效用的挑战。测量候选化合物与所选靶分子（例如受体）之间的化学相互作用的高通量筛选方法可以高速筛选化合物，但不能提供关于细胞生物学反应的信息。因此，选择了许多生物学上无活性或有毒的化合物。因此，具有基于细胞生物学反应的快速筛选方法是重要的。该提案的主要目标是开发和验证一种原型设备，该设备基于在生物组织结构中产生机械变化的细胞反应来筛选化合物。该方法以适合于快速筛选的形式测量小型化组织构建体的收缩力和刚度的变化。这种方法在几个方面是有利的： .所述测定基于对细胞收缩反应的测量，所述细胞收缩反应由许多生物学上重要的信号传导途径激活;  - 可以快速地并且以平行的形式对许多样品进行测定; .可以用小型化的样品进行分析，以保存珍贵的材料; .所述测定提供关于细胞和细胞外对测试化合物的反应的定量信息; .可以组装组织构建体以提供特定疾病状况的模型，例如，高血压或纤维化中血管平滑肌细胞收缩性升高，以及导致充血性心力衰竭或舒张功能障碍和瘢痕形成的心血管重塑。 的具体目标是优化原型装置测量minitissue结构的机械响应，以验证该设备与以前研究的组织结构的测量结果进行比较，然后证明该设备的实用性，在屏幕上的化合物，可以调节血压，通过减少收缩力所施加的血管平滑肌细胞。

DESCRIPTION (provided by applicant): The availability of libraries containing large numbers of chemical compounds potentially applicable as drugs poses the challenge of screening these compounds for their pharmaceutical utility. High throughput screening methods that measure chemical interactions between the candidate compound and a selected target molecule such as a receptor can screen compounds at high speed, but provide no information about the biological response of cells. As a result many compounds are selected that are inactive biologically or are toxic. Therefore, it is important to have rapid screening methods based on cellular biological responses. The major goal of this proposal is to develop and validate a prototype device that screens compounds based on cellular responses that produce mechanical changes in biological tissue constructs. This approach measures changes of contractile force and stiffness of miniaturized tissue constructs in a format suitable for rapid screening. This approach is advantageous in several respects: . the assay is based on the measurement of a cellular contractile response that is activated by many biologically important signaling pathways;  the assay can be carried out rapidly and in a parallel format on many samples; . the assay can be carried out with miniaturized samples to conserve precious materials; . the assay provides quantitative information about cellular and extracellular responses to test compounds; . tissue constructs can be assembled to provide models for specific disease conditions, e.g., elevated contractility of vascular smooth muscle cells in hypertension or fibrosis and cardiovascular remodeling responsible for congestive heart failure or diastolic dysfunction and for scar formation. The specific aims are to optimize a prototype device for measuring mechanical responses of minitissue constructs, to validate the device by comparison with measurements of previously studied tissue constructs and then to demonstrate the utility of this device in a screen for compounds that can regulate blood pressure by reducing contractile force exerted by vascular smooth muscle cells.