Bruce Conklin, MD
|School||UCSF School of Medicine|
|Address||1650 Owens St, SF 94158|
We are focused on constructing isogenic iPS cell disease models to study the molecular mechanisms associated with cardiomyopathies.
*Human Cardiac Disease Models
We use induced pluripotent stem (iPS) cells to model human cardiac genetic disease. We focus on genes associated with heart failure from cardiomyopathy or abnormal heart rhythm resulting in “sudden death.” The heart provides an ideal system to determine the molecular basis of human genetic findings. Hundreds of gene loci have already been associated with heart disease, yet, until recently, modeling these gene variants in human cardiac tissue has been difficult. Human iPS cells now allow us to produce many cardiovascular tissues that have already been used to successfully uncover disease phenotypes. Our first studies focused on iPS cells from patients who have genetic diseases and, more recently, the lab as focused on engineering iPS cells to have specific mutations since they allow more in-depth studies of disease mechanism in a controlled background.
*Genome and Tissue Engineering
The late Richard Feynman once said, “What I cannot create, I do not understand.” Although this is well known in the field of engineering, we are just beginning to apply the principle to human biology. Up until recently, human genetics was primarily observational, but newly developed genome engineering tools now allow us to directly test the cellular consequences of discrete genetic changes. We have developed efficient methods to edit one residue at a time in living human iPS cells, resulting in “isogenic” iPS cell lines that are identical except for a single alteration. These isogenic iPS disease models are now yielding phenotypes that are helping to explain the molecular basis of several human diseases. In addition, we are constructing collections of isogenic disease cell lines that carry a range of disease mutations, from the most severe (rare) to the moderate (common) forms of cardiomyopathy. We are currently focused on the most severe cardiomyopathies to develop cell-based assays. We are hopeful that these severe cardiomyopathies will allow us to understand the molecular basis of the more common cardiomyopathies as well.
The heart is a complex tissue that is tightly integrated via chemical and electrical coupling. We are working with tissue engineers to recapitulate these complex tissues so that we can better model cardiac disease. The disease cell lines we are making help to provide a “yard stick” to measure robustness of engineered tissues. The cardiac tissues that best reflect human cardiac contraction, and electrical coupling are most likely to provide insights into specific human disease genes.
*Targeting Better Therapies
We are hopeful that human iPS-based disease models will provide a path to develop safer, more effective drug therapies. Personalized medicine can benefit from experimental testing of gene variants to prove (or disprove) hypothetical associations with drug responses. The gene variants that we are testing could help avoid unwanted cardiac toxicity, while also pointing to new therapeutic opportunities. Human iPS disease models could provide the drug development platform of the future. Our prior work with G protein-coupled receptors (GPCRs) gives us a strong background in drug discovery. We previously developed a novel series of assays tools (G protein chimeras) that is used by 80% of major pharmaceutical companies and has contributed to the development of several approved drugs. In the future we imagine that safer and more effective drugs will be developed using genetically defined iPS-derived disease models.
iPS cells, Cardiomyopathy, Genetics, Genome Engineering
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