Research
Cardiovascular diseases, such as heart failure, cardiac arrhythmias, congenital heart disorders, and vascular diseases, are the leading causes of morbidity and mortality in adults and children throughout the world. The overall goals of our research program are to gain insights into the molecular mechanisms of these cardiovascular diseases as well as discover developmental pathways that help create the cardiovascular system. We are most interested in translating these findings for eventual cardiac therapies and early diagnostic tools, including cardiac regenerative cellular repair, gene therapies, and genetic/genomic testing. Towards this end, our laboratory uses a combination of human cardiovascular patients and their samples derived from our UCSD Sulpizio Cardiovascular Center as well as various model organisms, such as zebrafish, newts, and mice, for our investigations. Some of our current research projects are listed below:
Cardiac morphogenesis
"Illuminating the identity and organization of cardiovascular lineages within cardiac structures during human development"
The heart is the first organ to form in vertebrates, and comprises a spectrum of specialized cell-types that organize into complex morphological structures critical for heart function. However, the identity of these cell-types and how they coordinate and interact with each other to lead to the proper formation of the human heart remain to be fully elucidated. One project in the lab seeks to construct a comprehensive human cardiac cell and spatial atlas illuminating the cellular communities of specific anatomical domains within developing human hearts as well as the regulatory programs controlling the coordination of cell-types to form and develop cardiac structures.
Cardiac specification and differentiation
"Investigation of cellular cues for differentiation of ventricular cardiomyocytes"
In vitro differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes (CMs) is a key method for developing cell-replacement therapies for heart repair, due to the heart’s inability to regenerate. Despite improvements in differentiation efficiencies, current protocols give rise to functionally immature, diverse populations of CM sub-types at different developmental states leading to unfavorable effects when transplanted in humans. To generate specific, mature CM sub-types in vitro for heart repair treatment, it is essential to understand the cell fate decisions and developmental cues that allow a cell to become a particular cell type. Thus, our lab is working on generating pure populations of ventricular CMs for heart failure treatment by utilizing the cellular cues between CMs and non-CMs that govern ventricular development.
"Elucidating the Role of Hedgehog Signaling in Pacemaker Cell Development"
This project aims to investigate the intricate signaling network that controls pacemaker cell specification in the zebrafish heart with an emphasis on the early role of Hedgehog signaling. Understanding the spatio-temporal patterning and interplay of Hedgehog signaling with other signaling pathways during cardiac development can shed light on the etiology of congenital heart diseases that affect cardiac conduction.
"Investigating the mechanisms of how ventricular cardiomyocyte specific genes are regulated"
To understand the large data sets generated from samples collected during cardiac differentiation from human embryonic stem cells and formulating hypotheses based on this data. Specifically, studying how the myosin heavy chain genes are regulated during human cardiac development.
"Notch signaling induces proepicardial fate from Nkx2.5+ progenitors in zebrafish anterior lateral plate mesoderm"
This project focuses on the fate decision of proepicardial cells in zebrafish, locating the progenitors of proepicardium at Nkx2.5+ mesoderm and clarifying the signaling pathways that are involved in the process.
Cardiac plasticity and regeneration
Complex human genetics
"Understanding the mechanisms of co-segregating variants driving disease presentation"
Combining gene editing, engineering, and mechanobiology, we investigate how environmental stressors impact the variable expressivity of dilated cardiomyopathy-related combinatorially acting variants. Using CRISPR-Cas-9 base editing, we induce patient specific genetic co-segregating variants to better understand gene/environment interactions in the development of disease.
"Epigenetic mechanisms underlying atrial fibrillation pathogenesis"
Dissecting epigenetic mechanisms underlying atrial fibrillation pathogenesis and studying how non-coding cardiac response elements affect gene expression in non-cardiomyocytes in a stage-specific manner. Interestingly, even though atrial fibrillation is a conduction disease, many variants associated with it are found in cardiac cell types other than cardiomyocytes, suggestive of a non-cell autonomous and developmental mechanisms for the most prevalent arrhythmia in humans.