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1. Cardiac Development.

Congenital heart diseases are one of the most common birth defects in humans, and these arise from developmental defects during embryogenesis. Many of these diseases have a genetic component, but they might also be affected by environmental factors such as mechanical forces. The Liu Lab combines genetics, molecular and cell biology to study cardiac development and function, focusing on the molecular mechanisms that link mechanical forces and genetic factors to cardiac morphogenesis. Our studies using zebrafish as a model system serve as the basic foundation to address the key questions in cardiac development and function, and could provide novel therapeutic interventions for cardiac diseases.

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