Functional screen for genetic causes of hypoplastic left heart syndrome

左心发育不良综合征遗传原因的功能筛查

• 批准号: 10572737
• 负责人: Shu Jia
• 金额: $ 21.56万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572737
• 关键词: Address; Anatomy; Animal Model; Animal Organ; Biological; Blood; Candidate Disease Gene; Cardiac Output; Cardiac Volume; Cause of Death; Clustered Regularly Interspaced Short Palindromic Repeats; Color; Congenital Abnormality; Dangerousness; Detection; Development; Diameter; Disease; Double Outlet Right Ventricle; Early Diagnosis; Early Intervention; Elements; Embryo; Embryonic Heart; Etiology; Exhibits; Foundations; Functional disorder; Gene Combinations; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Screening; Genetic study; Goals; Heart; Heart Research; Human Genetics; Hypoplastic Left Heart Syndrome; Image; Imaging Device; Imaging technology; Impairment; Individual; Infant; Knowledge; Laser Scanning Microscopy; Lead; Left ventricular structure; Light; Mediating; Methodology; Methods; Microscope; Microscopy; Modeling; Molecular; Morphology; Mus; Mutate; Myocardial dysfunction; Pathogenesis; Pathologic; Performance; Phenotype; Physiology; Population; Process; Public Health; Pump; Rana; Rapid screening; Research; Resolution; Role; Scanning; Scheme; Sensitivity and Specificity; Shortening Fraction; Specimen; Speed; Structure; Study models; System; Tadpoles; Testing; Time; Variant; Ventricular; Ventricular Septal Defects; Visualization; Work; candidate identification; cardiogenesis; causal variant; congenital heart disorder; experimental study; heart function; human disease; in vivo; innovation; lens; malformation; meter; microCT; millimeter; millisecond; multi-photon; novel; spatiotemporal; structural heart disease; tool; transcription factor

PROJECT SUMMARY Congenital heart diseases (CHDs) are the most common type of birth defect and impact about 1% of the popu- lation worldwide. Among CHDs, hypoplastic left heart syndrome (HLHS), in which the left ventricle that pumps oxygenated blood to most of the body is malformed, is the most dangerous form and the most common cause of death in infants with CHDs. To achieve early diagnosis and intervention of the disease, the long-term goal is to understand the molecular and cellular mechanisms of HLHS. Although HLHS is evidently a genetic disease, little is known about the genetic mechanisms and pathophysiology underlying the disease. One major reason for such a knowledge gap is the lack of animal models replicating this human disease. Preliminary work from the lab suggests that frog may represent a valuable animal model for studying HLHS. The loss of transcription factor Ets1 in frog leads to an HLHS-like phenotype, with thickened ventricular wall and reduced chamber volume. Genetic deletion of Ets1 in mice, however, leads to ventricular septal defects and double outlet right ventricle, but not HLHS, suggesting the involvement of additional factors in the pathological development of the disease. Therefore, the goal of this project is to use the frog model to identify genetic causes for HLHS. To determine additional genes involved in HLHS and better understand how different structural changes in the heart correlate to cardiac function, an efficient functional screen is needed. Currently, there is no imaging tool that can continu- ously observe the entire beating embryonic frog heart in vivo with a high spatiotemporal resolution, making the direct analysis of cardiac function impossible. To address this challenge, the first aim will be developing a fast- speed, volumetric light-field microscopy tool that exhibits high specificity and sensitivity yet low photodamage to enable in vivo examination of heart function in developing embryos. With this platform, the second aim will be examining heart anatomy as well as heart function in frog embryos when candidate HLHS-related genes are mutated. Combining advanced imaging technology and quantitative analysis, this study will lead to the efficient discovery of critical genes involved in heart development and the structure-function relations between genetic components and pathophysiological phenotypes, laying the foundation to uncover the etiology of HLHS. This novel conceptual and methodological groundwork will also be valuable in broader basic and translational cardiac research.

项目概要 先天性心脏病 (CHD) 是最常见的出生缺陷类型，影响约 1% 的人口 世界范围内的关系。在先心病中，有左心发育不全综合征 (HLHS)，其中左心室泵血 身体大部分部位的含氧血液是畸形的，是最危险的形式和最常见的原因 患有 CHD 的婴儿死亡的比例。实现疾病的早期诊断和干预，长期目标是 了解 HLHS 的分子和细胞机制。尽管 HLHS 显然是一种遗传病， 人们对这种疾病的遗传机制和病理生理学知之甚少。一个主要原因是 这种知识差距是缺乏复制这种人类疾病的动物模型。前期工作从 实验室表明青蛙可能是研究 HLHS 的有价值的动物模型。转录因子的丢失 青蛙中的 Ets1 会导致类似 HLHS 的表型，即心室壁增厚和心室容积减小。 然而，小鼠中 Ets1 的基因缺失会导致室间隔缺损和右心室双出口， 但 HLHS 则不然，这表明在该疾病的病理发展中还涉及其他因素。 因此，该项目的目标是利用青蛙模型来识别 HLHS 的遗传原因。确定 与 HLHS 相关的其他基因，更好地了解心脏的不同结构变化如何相互关联 对于心脏功能，需要有效的功能筛查。目前，还没有任何成像工具可以连续 以高时空分辨率在体内观察整个跳动的胚胎青蛙心脏，使得 直接分析心脏功能是不可能的。为了应对这一挑战，首要目标是开发一种快速 速度、体积光场显微镜工具，具有高特异性和灵敏度，但光损伤低 能够对发育中胚胎的心脏功能进行体内检查。有了这个平台，第二个目标将是 当候选 HLHS 相关基因存在时，检查青蛙胚胎的心脏解剖结构和心脏功能 变异了。结合先进的成像技术和定量分析，这项研究将带来高效的 发现参与心脏发育的关键基因以及遗传之间的结构与功能关系 的组成和病理生理表型，为揭示 HLHS 的病因奠定基础。这 新颖的概念和方法论基础在更广泛的基础和转化心脏方面也将很有价值 研究。