Constitutive and Agent-Based Multiscale Models to Improve Vein Graft Survival

提高静脉移植物存活率的本构和基于代理的多尺度模型

• 批准号: 8883698
• 负责人: Scott A Berceli
• 金额: $ 52.76万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-08 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883698
• 关键词: Acute; Algorithms; Animals; Apoptosis; Biological Preservation; Blood; Blood Vessels; Bypass; Cell Culture System; Cell Culture Techniques; Cell Proliferation; Chromosome Mapping; Cicatrix; Clinical; Complex; Computer Simulation; Data; Data Set; Disease Progression; Engineering; Environment; Evaluation; Experimental Models; Failure; Gene Combinations; Gene Deletion; Gene Expression; Gene Silencing; Genes; Graft Survival; Half-Life; Health; Heart Diseases; Hyperplasia; Injury; Intervention; Ischemia; Lead; Limb structure; Linear Models; Lower Extremity; Mathematics; Measures; Mediating; Modeling; Morbidity - disease rate; Myocardial; Myocardial Infarction; Operative Surgical Procedures; Oryctolagus cuniculus; Pathologic; Pathology; Patient Care; Peptide Hydrolases; Performance; Perfusion; Process; Production; Regulator Genes; Research; Research Personnel; Sampling; Small Interfering RNA; Stroke; Subfamily lentivirinae; Systems Biology; Techniques; Testing; Therapeutic; Time; Translating; United States; Validation; Vascular Diseases; Veins; base; behavioral outcome; cell motility; cerebrovascular; combinatorial; computer science; improved; in vivo; large scale simulation; mortality; multi-scale modeling; multidisciplinary; novel therapeutics; predictive modeling; response; response to injury; success; tool

DESCRIPTION (provided by applicant): Heart disease, stroke, and limb loss continue to be a leading cause of U.S. mortality and morbidity. Despite advances in the surgical treatments for these pathologies, the long-term success of these interventions remains limited. Prior strategies aimed at improving the durability of vein grafts have focused largely on reductionist strategies and used linear models to describe the physical and biologic components of vascular disease progression. In order to advance our understanding of such complex phenomena, it is necessary to integrate different types of data and use quantitative models to predict behavior and outcomes. OVERALL HYPOTHESIS: A specific, finite set of shear-regulated genes are critical to controlling pathologic vein graft adaptation. Using the integration of multiscale modeling and experimental techniques, these genes can be identified and manipulated in vivo to improve vein graft durability. SPECIFIC AIM 1: Identify those model parameters that are most critical for accelerated loss of the vein graft lumen. Approach: Using a stochastic optimization algorithm to evaluate our in silico model of vein graft adaptation, a large-scale simulation is use to define the minimum parameter set, and correspondingly the core biologic processes, that lead to reduced intimal thickening and enhanced outward remodeling. SPECIFIC AIM 2: Create a dynamic gene regulatory network, which when integrated with an agent-based model of vascular adaptation, identifies the subset of genes that have the most significant impact on reducing intimal hyperplasia and preserving vein graft lumen. Approach: Transcriptional profiling of vein graft samples is used to create a gene regulatory network. Through a systematic evaluation of this network, highly interconnected genes are identified, specifically identifying those genes that when deleted lead to substantial changes in global gene expression. This subset of genes is explored using an agent-based model of vein graft adaptation to identify a set of key hub genes that when deleted result in significant improvements in lumen preservation. SPECIFIC AIM 3: Validate the model prediction and explore combinations of key hub genes that provide the most critical impact on the biologic processes that are central to pathologic vein graft adaptation. Approach: Employing a high throughput, cell culture system and an siRNA inhibition strategy, the effect of key hub gene deletion on cell proliferation, apoptosis, matrix production, protease activation and cell motility will be evaluated. The most promising genes, either alone or in combination, will move into Aim 4 for in vivo testing. SPECIFIC AIM 4: Identify the optimum combination of genes that will move forward into a large animal validation model and translated into a therapeutic tool to improve vein graft survival. Approach: Packaging a lentivirus delivery vehicle with a siRNA construct, we will utilize a rabbit vein bypass graft mode to evaluate the in vivo performance of the most promising gene sets that have been vetted through Aim 1 through 3, assessing their impact on reducing intimal hyperplasia and preserving vein graft lumen.

描述（由申请人提供）：心脏病、中风和肢体丧失仍然是美国死亡率和发病率的主要原因。尽管这些病理的手术治疗取得了进展，但这些干预措施的长期成功仍然有限。先前旨在提高静脉移植物耐久性的策略主要集中在简化策略上，并使用线性模型来描述血管疾病进展的物理和生物成分。为了促进我们对这种复杂现象的理解，有必要整合不同类型的数据，并使用定量模型来预测行为和结果。 总体假设：一个特定的，有限的剪切调节基因集是控制病理性静脉移植适应的关键。使用多尺度建模和实验技术的集成，这些基因可以在体内被识别和操纵，以提高静脉移植物的耐久性。具体目标1：确定对静脉移植物管腔加速损失最关键的模型参数。方法：使用随机优化算法来评估我们的静脉移植物适应的计算机模型，使用大规模模拟来定义最小参数集，以及相应的核心生物过程，其导致内膜增厚减少和向外重塑增强。具体目标2：创建动态基因调控网络，当与基于代理的血管适应模型集成时，识别对减少内膜增生和保护静脉移植物管腔具有最显著影响的基因子集。方法：静脉移植物样本的转录谱用于创建基因调控网络。通过对该网络的系统评估，识别出高度互连的基因，特别是识别出那些在删除时导致全局基因表达发生实质性变化的基因。使用基于代理的静脉移植物适应模型来探索该基因子集，以确定一组关键枢纽基因，当删除时，该基因导致管腔保存的显著改善。具体目标3：验证模型预测并探索关键枢纽基因的组合，这些基因对病理性静脉移植物适应的生物学过程具有最关键的影响。方法：采用高通量细胞培养系统和siRNA抑制策略，将评价关键枢纽基因缺失对细胞增殖、凋亡、基质产生、蛋白酶活化和细胞运动性的影响。最有希望的基因，无论是单独还是组合，将进入Aim 4进行体内测试。具体目标4：确定基因的最佳组合，这些基因将进入大型动物验证模型，并转化为改善静脉移植物存活率的治疗工具。方法：将慢病毒递送载体与siRNA构建体包装在一起，我们将利用兔静脉旁路移植物模式来评估已通过Aim 1至3审查的最有希望的基因集的体内性能，评估它们对减少内膜增生和保护静脉移植物管腔的影响。