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Prenatal valve formation in congenital heart disease

先天性心脏病的产前瓣膜形成

基本信息

批准号：
10716712
负责人：
Sandra Rugonyi
金额：
$ 38.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716712
关键词：
3-Dimensional Address Affect Aorta Arteries Birds Birth Blood Blood flow Cardiac Cell Differentiation process Cells Characteristics Chemicals Chick Chick Embryo Collagen Collagen Fiber Competence Computer Models Confocal Microscopy Congenital atresia of pulmonary valve Cues Data Deposition Development Diameter Echocardiography Elastin Elastin Fiber Embryo Event Exhibits Extracellular Matrix Face Fetal Development Fetal Heart Fetus Functional disorder Future Heart Heart Valves Human Image Impairment Intervention Knowledge Left ventricular structure Life Longitudinal Studies Lung Maps Microscopy Modeling Morphology Natural regeneration Newborn Infant Operative Surgical Procedures Organ Pathologic Pattern Predisposition Process Pulmonary Valve Stenosis Pulmonary artery structure Resolution Right ventricular structure Scanning Electron Microscopy Side Smooth Muscle Myocytes Structure Surface Testing Tetralogy of Fallot Time Tissues Ventricular Septal Defects congenital heart disorder experience fetal fetal diagnosis hatching heart function heart imaging hemodynamics imaging modality improved in vivo in vivo imaging light microscopy mathematical model microCT novel predictive modeling prenatal response semilunar valve shear stress treatment strategy valve replacement

项目摘要

SUMMARY Tetralogy of Fallot (TOF) is a critical congenital heart malformation that typically requires intervention soon after birth and affects about 1,660 newborns per year in the US. In TOF, blood flow through the pulmonary artery is reduced or blocked (due to pulmonary stenosis or atresia), while blood flow through the aorta is increased. Prenatally, TOF-induced abnormal blood flow progressively leads to pathological cardiac valve tissue remodeling. The semilunar (aortic and pulmonary) valve leaflets and the great arteries (the aorta and pulmonary artery) are particularly susceptible to abnormal blood flow. This is because fetal stages are a critical time when extracellular matrix components that dictate valve integrity and function, such as collagen and elastin, deposit and organize within valve tissues, and smooth muscle cells are differentiating and organizing in supporting arteries. However, how semilunar valves and great arteries remodel in response to TOF-induced abnormal hemodynamic loads during fetal stages remains unknown. To address this knowledge gap, this project will use a chick embryonic model of TOF that reproduces the characteristic heart morphologies and flow patterns found in human fetuses with TOF. Avian embryos are amenable to in vivo imaging and allow tightly controlled longitudinal studies in ovo. Moreover, valve leaflets in human and chick exhibit the same characteristic layers, which similarly arrange in response to blood flow cues during fetal development in human and pre-hatching in chick. The overarching hypothesis of this proposal is that before birth abnormal blood flow in TOF leads to aberrant, disorganized deposition of collagen and elastin fibers in semilunar valve leaflets, and abnormal smooth muscle cell localization in supporting great artery tissues. Three aims are proposed: 1) Determine characteristic blood flow patterns in fetal hearts with TOF using advanced in vivo imaging and computational modeling; 2) Assess abnormal tissue remodeling of semilunar valves and great arteries in TOF through a combination of advanced multiscale microscopy; 3) Develop predictive models of flow-induced semilunar valve remodeling in TOF. Through a novel combination of multiscale imaging and computational modeling, this project will elucidate how TOF-induced abnormal blood flow leads to (and exacerbates) semilunar valve and great artery tissue anomalies. In the future, findings from this project will improve fetal diagnosis and prediction of prenatal pathological valve remodeling, enabling better decisions of when and how to intervene to avoid or even reverse pathological valve remodeling, and will inform valve regeneration efforts.

摘要法洛四联症(TOF)是一种严重的先天性心脏畸形，通常需要尽快介入治疗。出生后，在美国每年影响大约1,660名新生儿。在TOF中，血液流经肺动脉减少或阻塞(由于肺动脉狭窄或闭锁)，而通过主动脉的血流则增加了。在产前，TOF引起的异常血流逐渐导致病理性心脏瓣膜组织重塑。半月瓣(主动脉和肺动脉)叶和大动脉(主动脉和动脉)特别容易受到异常血流的影响。这是因为胎儿阶段是一个关键的决定瓣膜完整性和功能的细胞外基质成分，如胶原和弹性蛋白，沉积和组织在瓣膜组织内，平滑肌细胞正在分化和组织支持动脉。然而，半月瓣和大动脉如何对TOF诱导的反应进行重塑胎儿期异常血流动力学负荷尚不清楚。为了解决这一知识差距，该项目将使用TOF的鸡胚模型来复制 TOF患者胎儿的心脏形态和血流模式特征。禽类胚胎是服从体内成像，并允许在卵子中进行严格控制的纵向研究。此外，在中国的阀门传单人类和小鸡表现出相同的特征层，这些层类似地根据血流信号进行排列在人类胚胎发育期间和雏鸡孵化前。这项提议的首要假设是出生前TOF的异常血流会导致胶原和弹性蛋白的异常、紊乱的沉积半月瓣叶纤维和支持大动脉的异常平滑肌细胞定位纸巾。提出了三个目标：1)用TOF确定胎儿心脏的特征血流模式使用先进的活体成像和计算模型；2)评估异常组织重塑经先进多尺度联合应用于TOF中的半月瓣和大动脉 3)建立TOF血流诱导半月瓣重塑的预测模型。通过多尺度成像和计算建模的新组合，该项目将阐明如何 TOF诱导的异常血流导致(并加重)半月瓣和大动脉组织反常现象。在未来，这个项目的发现将改进胎儿诊断和产前预测病理性瓣膜重塑，能够更好地决定何时以及如何进行干预，以避免甚至逆转病理性瓣膜重塑，并将通知瓣膜再生努力。