Computer Modeling of Perlecan as a Vascular Regulator

Perlecan 作为血管调节器的计算机建模

• 批准号: 7544966
• 负责人: MICHAEL W FANNON
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544966
• 关键词: Address; Affinity; Binding; Binding Sites; Biological Assay; Biological Availability; Bioreactors; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular Diseases; Cell surface; Cells; Characteristics; Competitive Binding; Complex; Computer Simulation; Development; Disease; Elements; Endothelial Cells; Extracellular Matrix; Fibroblast Growth Factor; Goals; Growth Factor; Growth Factor Interaction; Growth and Development function; In Vitro; Kinetics; Lead; Ligands; Measures; Modeling; Neoplasms in Vascular Tissue; Organ; Organism; Pharmacologic Substance; Predictive Value of Tests; Prevention; Proteoglycan; Pulsatile Flow; Pump; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Simulate; Site; Solutions; Surface; System; Systems Biology; Testing; Therapeutic; Tissues; Tube; base; capillary; design; in vitro Assay; in vivo; in vivo Model; novel; perlecan; prevent; programs; reaction rate; response; tool; tumor growth

Blood circulation is a complex system. At every moment a multitude of molecules are transported simultaneously and continuously to specific targets in the vasculature. The ability to regulate whole panels of molecules by controlling the circulating concentration of a single moiety, if discrete, could provide a powerful tool to understand the causes, prevention and treatment of cardiovascular disease and other disorders relating to blood vessels. Perlecan, an important molecule in blood vessel and tumor growth could be such a molecule. Our hypothesis is that, based on its high affinity for a number of growth factors that are crucial to normal and pathological vascular growth and development, circulating perlecan has the potential to sequester these growth factors in blood, preventing their interactions with vascular surfaces. Because of the complexity of this system, however, it is difficult to characterize at a macro level using in vitro or in vivo approaches alone. Computer modeling provides us with a powerful tool to test parameters and conditions, such as multiple ligand interactions in solution and on vascular surfaces under flow, which are crucial components in developing an accurate understanding. A simulated vessel model under flow will be used to test the predictive value of the model using a variety of testable conditions. Our specific aims are to: 1. Develop a model of endothelial cell binding based on the binding characteristics of three growth factors and the proteoglycan perlecan 2. Test the model using competitive binding assays with growth factors alone or in combination with other factors as a function of perlecan concentration 3. Refine the model to mimic the interactions of the growth factors and perlecan under flow and adjust the model to accommodate changes between what is observed in experimental assays and what is predicted based on flow conditions Our model will be the first step in attaining our long range goal of designing and testing Pharmaceuticals that exploit similar regulatory characteristics. By using a systems biology approach the interrelatedness of the blood vessels and the components being transported through them will be characterized at the level of the organism as a whole.

血液循环是一个复杂的系统。每时每刻都传输了许多分子 同时且连续与脉管系统中的特定靶标。调节整个面板的能力 通过控制单个部分的循环浓度（如果离散）可以提供分子的循环浓度，可以提供 了解心血管疾病的原因，预防和治疗的强大工具 与血管有关的疾病。 Perlecan，血管和肿瘤生长的重要分子可以 成为这样的分子。我们的假设是，基于其对许多增长因素的高亲和力 对于正常和病理血管生长和发育至关重要，循环perlecan具有潜力 将这些生长因子隔离在血液中，以防止它们与血管表面的相互作用。因为 但是，该系统的复杂性很难在体外或体内在宏观层面表征 独自接近。计算机建模为我们提供了测试参数和条件的强大工具， 例如在溶液和流动的血管表面上的多种配体相互作用，这是至关重要的 建立准确理解的组成部分。流动下的模拟船只模型将用于 使用多种可测试条件测试模型的预测值。我们的具体目的是： 1。根据三个生长因子的结合特征开发内皮细胞结合的模型 和蛋白聚糖perlecan 2。使用单独生长因子或与其他结合的竞争性结合测定测试模型 因素随perlecan浓度的函数 3。完善模型以模仿流动下生长因子和perlecan的相互作用，并调整 模型以适应实验测定中观察到的变化和预测的内容 基于流动条件 我们的模型将是实现我们设计和测试药品的远距离目标的第一步 利用类似的监管特征。通过使用系统生物学方法 血管和通过它们运输的成分将在其水平上进行表征 整个生物体。