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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

基本信息

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
项目类别：
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

项目摘要

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.