A zebrafish-based platform to uncover genetic causes and potential treatments for lysosome-associated cardiac diseases

Lysosomal dysfunction has been linked to the aetiology and progression of several cardiac diseases.

However, the genetic basis of this association is vastly understudied, and treatment options to restore lysosomal function in cardiac tissues are mostly non-existent.

With ZKADY (Zebrafish sKreening plAtform for gene-risk and treatment Discovery to target lYsosome-associated cardiac disease), I aim to establish a zebrafish-based disease modelling platform to systematically explore the association between cardiac disease and impaired lysosomal function.

For this, I will identify cardiac disease risk genes that are anticipated to affect lysosomal function based on genome-wide association studies and gene pathway analyses.

Then, to systemically characterize those candidate genes, I will establish their respective zebrafish disease models following a CRISPR/Cas9 mutagenesis approach and functionally validate the cardiac and lysosomal phenotypes they display.

Using novel tissue-specific and endogenous autophagy and lysosomal zebrafish transgenic reporters in combination with high-content image-based pipelines, I will evaluate potential lysosomal function-enhancing compounds and a novel protein replacement technology as new therapeutic options for cardiac disease.

The results obtained through ZKADY will help to understand the role of lysosomal function during cardiac development and elucidate the potential of the lysosome as a therapeutic target for cardiac disease.

Furthermore, ZKADY will create a versatile high-throughput target validation and drug discovery tool for lysosomal-associated cardiac diseases and potentially other lysosomal storage disorders.

This project will be developed in the research group of Marcel den Hoed at Uppsala University and will count on the infrastructure and expertise required for its completion.