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

基本信息

批准号：
8717717
负责人：
Scott A Berceli
金额：
$ 54.96万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-08 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717717
关键词：
Acute Algorithms Animals Apoptosis Behavior 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 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 Outcome 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 cell motility cerebrovascular combinatorial computer science improved in vivo large scale simulation mortality multi-scale modeling multidisciplinary novel therapeutics predictive modeling public health relevance response response to injury success tool

项目摘要

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和发病的主要原因。尽管这些疾病的外科治疗取得了进展，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还原策略上，并使用线性模型来描述血管疾病进展的物理和生物成分。为了增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：一组特定的、有限的剪切调节基因对于控制病理性静脉移植适应至关重要。利用多尺度建模和实验技术的整合，可以在体内识别和操纵这些基因，以提高静脉移植物的耐久性。具体目标 1：确定对于加速静脉移植管腔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适应的计算机模型，并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，从而减少内膜增厚并增强向外重塑。具体目标 2：创建一个动态基因调控网络，当与基于代理的血管适应模型集成时，确定对减少内膜增生和保护静脉移植管腔具有最显着影响的基因子集。方法：使用静脉移植样本的转录谱来创建基因调控网络。通过对该网络的系统评估，可以识别出高度互连的基因，特别是识别那些删除后会导致全局基因表达发生重大变化的基因。使用基于代理的静脉移植适应模型来探索该基因子集，以识别一组关键的中心基因，这些基因在被删除时会导致管腔保存的显着改善。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适应的核心生物过程产生最关键的影响。方法：采用高通量细胞培养系统和 siRNA 抑制策略，评估关键枢纽基因缺失对细胞增殖、凋亡、基质产生、蛋白酶激活和细胞运动的影响。最有前途的基因，无论是单独的还是组合的，都将进入 Aim 4 进行体内测试。具体目标 4：确定将进入大型动物验证模型并转化为提高静脉移植存活率的治疗工具的最佳基因组合。方法：用 siRNA 构建体包装慢病毒递送载体，我们将利用兔静脉旁路移植模式来评估已通过目标 1 至 3 审查的最有前途的基因组的体内性能，评估它们对减少内膜增生的影响并保留静脉移植管腔。