A Multiscale Modeling Approach to Hypoplastic Left Heart Syndrome

左心发育不全综合征的多尺度建模方法

• 批准号: 9053027
• 负责人: VISHAL NIGAM
• 金额: $ 38.24万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053027
• 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; Mus; Newborn Infant; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatric cardiology; Pharmacological Treatment; Physiological; Process; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stress; Stretching; Testing; Time; Tissues; Transplantation; Ventricular; base; biomechanical model; computer framework; fetal; hemodynamics; improved; in utero; in vitro testing; in vivo; induced pluripotent stem cell; models and simulation; molecular modeling; mortality; multi-scale modeling; multidisciplinary; novel; novel therapeutics; palliation; prediction algorithm; prenatal; public health relevance; research study; 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（由适用提供）：低塑性左心综合征（HLHS）是一种先天性缺陷，其标记为欠发达的左心室（LV），无法为人体提供足够的血液流动。目前，HLHS患者的护理标准是手术疼痛或心脏移植，两者都有严重的并发症。胎儿超声心动图表明，发育过程中LV填充的减少导致LV降低，从而表明HLHS的生物力学机制。我们对该项目的理由是，了解生物力学响应途径在HLHS发病机理中的作用将通过实现该缺陷的药物治疗来改变HLHS患者的当前管理范例。我们的总体目标是1）发现新的分子调节剂，这些调节剂增加了HLHS患者的LV大小，以及2）构建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有效性。我们假设增加拉伸激活的生长途径的活性将改善子宫内发育不良的LV的生长。该假设基于我们的数据，该数据刺激了心肌细胞的增殖，生长和心室生长。此外，利用miRNA-seq，我们已经确定了microRNA，miR-486，即1）在体外/HLHS患者中伸展反应迅速，2）促进体内心脏增长。为了检验我们的假设并实现我们的总体目标，我们将执行两个具体的目标：目标1。预测和验证miR-486治疗对小鼠和人类胚胎心脏发展HLHS的影响。我们假设miR-486增加了胚胎心脏的生长。该目标将在鼠和人类HLHS胚胎中检查miR-486在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IPS心肌细胞。这些体外数据将纳入胚胎心脏生长的新型3D结局元件（FE）模型。最后，将使用miR-486在子宫内治疗HLHS小鼠胚胎将用于验证FE建模模拟。 AIM 2。基于miRNA改善胚胎心室生长潜力的计算模型，将候选miRNA用于体内测试。我们假设miRNA靶向预测，心肌细胞的数学分子模型和HLHS Fe建模可以耦合以测试候选伸展响应性miRNA，以增加HLHS心脏中LV大小的潜力。增加LV的候选miRNA在小鼠HLHS胚胎模拟中的生长最大，将在体内进行测试。该miRNA将在子宫内测试，至1）检查对LV生长的影响，并验证耦合模型。拟议的研究使用体外完成（鼠和人IPS细胞），体内以及在计算机方法中的研究将阐明临界途径 生物力学应力刺激心脏生长。多学科团队使这种独特的综合方法成为可能，该团队结合了儿科心脏病学，心脏生物力学，分子生物学和计算建模方面的专业知识。