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: 7179677
• 负责人: MICHAEL W FANNON
• 金额: $ 34.28万
• 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/7179677
• 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; Condition; 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; Numbers; Organ; Organism; Pharmacologic Substance; Predictive Value of Tests; Prevention; Proteoglycan; Pulsatile Flow; Pump; Range; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：血液循环是一个复杂的系统。在每时每刻，将许多分子同时且连续地传输到脉管系统中的特定靶标。通过控制单个部分的循环浓度（如果离散）可以提供一个有力的工具来理解心血管疾病的原因，预防和治疗其他与血管有关的疾病，从而可以通过控制单个部分的循环浓度来调节整个分子的能力。 Perlecan是血管和肿瘤生长的重要分子，可能是这样的分子。我们的假设是，基于其对许多对于正常和病理血管生长和发育至关重要的生长因素的亲和力，循环perlecan有可能隔离血液中的这些生长因子，以防止其与血管表面的相互作用。但是，由于该系统的复杂性，仅使用体外或体内方法在宏观上很难表征。计算机建模为我们提供了一个强大的工具来测试参数和条件，例如解决方案中的多种配体相互作用和流量下的血管表面上，这是开发准确理解的关键组成部分。流动下的模拟血管模型将用于使用各种可测试条件来测试模型的预测值。我们的具体目的是：1。基于三个生长因子和蛋白质聚糖perlecan的结合特征开发一种内皮细胞结合模型。2。使用竞争性结合因子或与其他因素结合或结合其他因素与perlecan浓度的函数进行竞争性结合因子进行测试。根据流量条件进行的预测，我们的模型将是达到设计和测试利用类似监管特征的药品的长距离目标的第一步。通过使用系统生物学方法，将在整个生物体的水平上表征血管的相互关系和通过它们传输的成分的相互关系。