Method of determining cellular protein homeostasis
The present invention provides assays and compositions to identify the risk of toxicity in a patient population with genotypic variations in specific proteins and/or protein complexes within the patient population.
1. A method of determining the risk of agent-induced toxicity in a patient population comprising:
providing a panel of isogenic cell populations comprising muscle cells, muscle cell progenitors, or a combination thereof produced from differentiated induced pluripotent stem cells, wherein the isogenic cell populations comprise mutations and/or polymorphisms of BAG3;
contacting said panel of isogenic cell populations with an agent; and
detecting ex vivo live cellular activity associated with toxicity resulting from contact with the agent in any of the isogenic cell populations, thereby detecting genotypes of BAG3 that are associated with an increased risk of agent-induced toxicity resulting from the BAG3 genotype in the patient population.
2. The method of claim 1 , wherein the agent is a proteasome inhibitor.
3. The method of claim 2 , wherein the agent inhibits autophagy in the cell populations.
4. The method of claim 1 , wherein the muscle cells or muscle cell progenitors are skeletal muscle cells or skeletal muscle cell progenitors.
5. The method of claim 1 , wherein the muscle cells or muscle cell progenitors are cardiomyocytes or cardiomyocyte progenitors.
6. The method of claim 1 , wherein the ex vivo cellular activity is sarcomeric disarray or contractility by the muscle cells, muscle cell progenitors, or a combination thereof.
7. The method of claim 1 , wherein the ex vivo cellular activity is detected over time.