Automated assays of gap junction functions and screening of drugs for rescuing conduction in heart tissues

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Sudden cardiac death (SCD) accounts for up to 50% of lives lost from heart disease. The major causes of SCD are genetic problems (present from birth) and ischemic heart disease resulting from poor lifestyle/obesity, both causing life-threatening irregular beating of the heart (arrhythmias). We are interested in the genetic causes of the lethal arrhythmias and how they can be treated. Often the genetic causes of SCD result in changes to gap junctions, which are specialized channels that allow for communication between heart cells and facilitate coordinated contraction of the heart. Discovery of new therapeutics for this condition is challenging since measuring changes to (and rescue of) gap junctions is technically difficult. We have previously devised and published novel methods to measure gap junction activity and have shown how gap junctions are modified with disease. Our automated system injects a small fluorescent dye into individual cardiomyocytes, and follows the spread of the dye to measure gap junction function. In this project, we will further develop our system to perform microinjection in a 96-well plate configuration, allowing us to screen and test many drug compounds for their ability to correct the disease. Additionally, we will devise a new assay based on calcium movement between cells to validate and correlate our results, also in a 96-well format. Any potential therapeutics identified will be tested in two human cardiomyocyte models of sudden cardiac death, showing if the drugs are highly likely to work in patients. Most of the drugs we will test are already approved by regulatory agencies, ensuring rapid translation to patient care. In summary, our work will devise new and novel techniques for measuring heart function and deliver new therapies to patients with this prevalent disease.