Project description
Establishing links between organelle malfunctioning and human diseases
Many currently incurable human diseases, including metabolic and neurodegenerative disorders, are associated with the malfunctioning of cell organelles. Despite the identification of causative genes, efficient therapies are often not existing due to the difficulty of finding treatments in cases of loss-of-function mutations. Until recently, mutation-based genome-wide suppressor surveys were limited to model organisms and phenotypes yielding growth defects. With the development of innovative, forward genetics screens and combinations of genome engineering, ultradeep haploid mutagenesis and direct stratification of fixed mutants, researchers are now able to investigate genetic suppression of human organelle defects. The EU-funded SOLID project aims to establish a systematic mapping of genetic suppression for important organelles and define the links to human diseases.
Objective
The goal of SOLID is the systematic mapping of genetic suppression for important organelles with impaired fidelity in human disease to uncover new strategies to correct the perturbed state. Functioning of the eukaryotic cell relies on the concerted activity of biological machines, defects in which can cause incurable human disease, including metabolic disorders and neurodegeneration. This is exemplified by malfunctioning mitochondria or lysosomes, for which (alongside environmental triggers) hundreds of causative genes have been identified, but cures are mostly lacking. This is mainly due to the difficulty of drugging loss-of-function mutations, which uniquely alter or entirely remove the gene product. Extensive studies in yeast and initial work in the human system show that cellular modules contain a substantial amount of hidden genetic suppression. Revealing suppressors of disease-defining features of organelle perturbation and targeting those instead of the query mutations, will address the frustrations of drugging an absent factor and etiological diversity. Until now, mutation-based genome-wide suppressor surveys were mostly limited to model organisms and phenotypes yielding growth defects, due to technical hurdles associated with recessive genetics in the human system. However, with the development of a groundbreaking new forward genetics platform that combines genome engineering, ultradeep haploid mutagenesis and direct stratification of fixed mutants, we can now, for the first time, interrogate genetic suppression of human organelle defects independent of cellular fitness. SOLID will also develop new technology to study organelle fidelity in an exhaustive fashion that departs from a gene-centric view point and captures complex phenotypes. Altogether, this will create a new paradigm of 'studying cell biology via genetics' widely applicable to many different biological questions, and reveal urgently needed novel therapeutic possibilities for incurable diseases.
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Funding Scheme
ERC-STG - Starting GrantHost institution
80539 MUNCHEN
Germany