A Multiscale Modeling Approach to Hypoplastic Left Heart Syndrome

左心发育不良综合征的多尺度建模方法

• 批准号: 9260047
• 负责人: VISHAL NIGAM
• 金额: $ 37.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260047
• 关键词: Animal Model; Biomechanics; Blood flow; Cardiac; Cardiac Myocytes; Cardiac development; Cell Proliferation; Cells; Child; Clinical; Computer Simulation; Congenital Abnormality; Congenital Heart Defects; Coupled; Couples; Critical Pathways; Data; Defect; Development; Diastole; Echocardiography; Elements; Embryo; Embryonic Heart; Evolution; Fetus; Future; Goals; Growth; Growth and Development function; Heart; Heart Transplantation; Histologic; Human; Hypertrophy; Hypoplastic Left Heart Syndrome; In Vitro; Intervention; Left; Left ventricular structure; Mathematics; Mechanics; Methods; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Models; Morbidity - disease rate; Morphology; Mus; Newborn Infant; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatric cardiology; Periodicity; Pharmacological Treatment; Pharmacology; Physiological; Process; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stress; Stretching; Testing; Time; Tissues; Transplantation; Ventricular; base; biomechanical model; computer framework; experimental study; fetal; hemodynamics; improved; in utero; in vitro testing; in vivo; induced pluripotent stem cell; mechanotransduction; models and simulation; molecular modeling; mortality; multi-scale modeling; multidisciplinary; novel; novel therapeutics; palliation; prediction algorithm; prenatal; public health relevance; response; simulation; standard of care; therapeutic target

 DESCRIPTION (provided by applicant): Hypoplastic Left Heart Syndrome (HLHS) is a congenital defect marked by an underdeveloped left ventricle (LV) that is unable to provide adequate blood flow to the body. Currently, the standard of care for HLHS patients is surgical palliation or cardiac transplantation, both of which have serious complications. Fetal echocardiograms demonstrate that decreased LV filling during development results in a hypoplastic LV, thereby indicating a biomechanical mechanism for HLHS. Our rationale for this project is that understanding the role of biomechanical responsive pathways in the pathogenesis of HLHS will shift the current management paradigm of HLHS patients by enabling pharmacological treatment of this defect. Our overarching goals are 1) to discover novel molecular modulators that increase LV size in HLHS patients, and 2) to build and validate multi-scale computational models to evaluate the efficacy of these modulators at the cellular and whole-organ level. We hypothesize that increasing the activity of stretch-activated growth pathways will improve the growth of hypoplastic LVs in utero. This hypothesis is based on our data that stretch stimulates cardiomyocyte proliferation, growth, and ventricular growth. Furthermore, utilizing miRNA-Seq, we have identified a microRNA, miR-486, that is 1) stretch responsive in vitro/HLHS patients and 2) promotes cardiac growth in vivo. To test our hypothesis and to achieve our overarching goals, we will perform two specific aims: Aim 1. Predict and validate the effects of miR-486 treatment on mouse and human embryonic hearts developing HLHS. We postulate that miR-486 increases embryonic cardiac growth. Thus this aim will examine miR-486 role in LV growth, both in murine and human HLHS embryos. miR-486 effects on cell proliferation, size, and contractile function will also be studied in mouse and human iPS cardiomyocytes. These in vitro data will be incorporated into a novel 3D finite element (FE) model of embryonic cardiac growth. Finally, treatment of HLHS mouse embryos with miR-486 in utero will be used to validate FE modeling simulations. Aim 2. Prioritization of candidate miRNAs for in vivo testing based upon computational modeling of the miRNAʼs potential to improve embryonic ventricular growth. We postulate that miRNA target predictions, mathematic molecular model of cardiomyocytes, and HLHS FE modeling can be coupled to test candidate stretch-responsive miRNAs for potential to increase LV size in HLHS hearts. The candidate miRNA that increases LV the most growth within simulations of mouse HLHS embryos will be tested in vivo. This miRNA will be tested in utero, to 1) examine the effects on LV growth and 2) validate the coupled model. The proposed studies using complementary in vitro (murine and human iPS cells), in vivo, and in silico methods will elucidate critical pathways by which biomechanical stress stimulates cardiac growth. Such a unique comprehensive approach is made possible by a multidisciplinary team that incorporates expertise in pediatric cardiology, cardiac biomechanics, molecular biology, and computational modeling.

 描述（由申请人提供）： 左心发育不良综合征 (HLHS) 是一种先天性缺陷，其特征是左心室 (LV) 发育不全，无法向身体提供足够的血流。目前，HLHS患者的标准治疗是手术姑息治疗或心脏移植，这两种方法都有严重的并发症。胎儿超声心动图表明，发育过程中左心室充盈减少会导致左心室发育不全，从而表明 HLHS 的生物力学机制。我们开展该项目的理由是，了解生物力学响应途径在 HLHS 发病机制中的作用，将通过对该缺陷进行药物治疗来改变 HLHS 患者当前的治疗模式。我们的首要目标是 1) 发现可增加 HLHS 患者左心室大小的新型分子调节剂，2) 建立和验证多尺度计算模型，以评估这些调节剂在细胞和整个器官水平上的功效。我们假设增加牵张激活生长通路的活性将改善子宫内发育不全的左心室的生长。这一假设基于我们的数据，即拉伸刺激心肌细胞增殖、生长和心室生长。此外，利用 miRNA-Seq，我们鉴定了一种 microRNA，miR-486，它 1) 在体外/HLHS 患者中具有拉伸反应性，2) 在体内促进心脏生长。为了检验我们的假设并实现我们的总体目标，我们将实现两个具体目标： 目标 1. 预测并验证 miR-486 治疗对发生 HLHS 的小鼠和人类胚胎心脏的影响。我们假设 miR-486 促进胚胎心脏生长。因此，该目标将检查 miR-486 在小鼠和人类 HLHS 胚胎中的 LV 生长中的作用。 miR-486 对细胞增殖、大小和收缩功能的影响也将在小鼠和 人类 iPS 心肌细胞。这些体外数据将被纳入胚胎心脏生长的新型 3D 有限元 (FE) 模型中。最后，在子宫内用 miR-486 处理 HLHS 小鼠胚胎将用于验证有限元建模模拟。目标 2. 基于 miRNA 改善胚胎心室生长潜力的计算模型，优先考虑用于体内测试的候选 miRNA。我们假设 miRNA 目标预测、心肌细胞的数学分子模型和 HLHS FE 模型可以结合起来测试候选拉伸响应 miRNA 是否有可能增加 HLHS 心脏中的 LV 大小。在小鼠 HLHS 胚胎模拟中，最能促进 LV 生长的候选 miRNA 将在体内进行测试。该 miRNA 将在子宫内进行测试，以 1) 检查对 LV 生长的影响，2) 验证耦合模型。拟议的研究使用互补的体外（小鼠和人类 iPS 细胞）、体内和计算机方法将阐明关键途径 生物力学压力刺激心脏生长。这种独特的综合方法是由多学科团队实现的，该团队融合了儿科心脏病学、心脏生物力学、分子生物学和计算建模方面的专业知识。