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.