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1. Systems approaches to cardiac maturation.

During the first weeks of extrauterine life, neonates experience transitions and changes as part of the developmental and adaptive-to-environment processes. These physiological changes that characterize the transitional period are profound and unequaled anywhere else in life. In response to the drastic changes in circulation, oxygenation, and biochemical milieu, the cardiomyocyte switches from a fetal state to an adult phenotype, enhancing its ability to generate and withstand increased contractile force. By leveraging an in vivo mouse mosaic knockout system, we are studying transcriptional and posttranscriptional regulation of cardiomyocyte maturation. Yet, the genetic network that governs this critical process remains largely unidentified. To address these challenges, we are developing an in vivo CRISPR screening platform coupled with single-nucleus RNA-seq (in vivo single-nucleus perturb-seq platform). This integrated approach allows us to target cells within their native environment and subsequently sequence them at the single-nucleus level. By leveraging transcriptional phenotypes, we will then be able to predict gene function within the natural context of the cardiovascular system.

2. Pathological Cardiac Remodeling.

In response to pathological stimuli, the adult mammalian heart drastically enlarges, resulting in a condition known as pathological hypertrophy. This enlargement acts as an immediate compensatory measure to confer resistance to cardiac stress. However, prolonged hypertrophy predisposes the heart to intractable heart failure and sudden cardiac death, the leading cause of death in the US and the world. An in-depth knowledge of the molecular basis of pathological hypertrophy could have considerable impact on the development of more potent therapeutics for the treatment of heart disease. When subjected to pathological stimuli, the heart undergoes extensive metabolic and structural changes characterized by a switch from fatty acid oxidation to greater reliance on glycolysis and hypertrophic growth of the cardiomyocytes, respectively. The extensive cardiac structural and metabolic changes during pathological hypertrophy involves profound global alterations in cardiac transcriptome. The Liu lab currently studies RNA-binding protein mediated posttranscriptional regulation of pathological cardiac hypertrophy.

3. Cardiac Regeneration.

Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, but also involves complex interactions between distinct cardiac cell types including non-cardiomyocytes (nonCMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of nonCMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assemble an atlas of cell states from 61,977 individual nonCM scRNA-seq profiles isolated at multiple time-points during zebrafish heart regeneration. Our analysis reveals extensive nonCM cell diversity, including multiple macrophage (MC), fibroblast (FB) and endothelial cell (EC) subpopulations with unique spatiotemporal distributions and suggests an important role for MC in inducing the activated FB and EC subpopulations. Furthermore, we developed computational algorithm Topologizer to map the topological relationships and dynamic transitions between functional states. We uncover dynamic transitions between MC functional states and identify factors involved in mRNA processing and transcriptional regulation associated with the transition. Our single-cell transcriptomic analysis of nonCMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of this process.


website 5zebrafish photo credit: Jennifer Rumbach