Hormone receptors help to coordinate the development and function of tissues such as the heart. The largest known family of receptors for hormones and drugs are the G protein-coupled receptors (GPCRs), with over 700 human genes.  To better understand the role of GPCRs in vivo, we use computational methods (bioinformatics) to identify/refine new pathways. We test these pathways we use high-throughput experimental methods (functional genomics) in embryonic stem cells (ESCs), ESC-derived cardiac myocytes, and in hearts of genetically altered mice.

Our pathway-oriented bioinformatics effort has produced a free, publicly distributed software package, GenMAPP (Gene Map Annotator and Pathway Profiler, www.GenMAPP.org). GenMAPP is now used by researchers world-wide (>12,000 unique registrations, in 35 countries, >200 publications citing the program). We are expanding this open source program to allow genome-wide, pathway-oriented analysis for twenty species, for all types of functional genomic data, such as genetic variation, disease association studies, and analysis of functional genomic experiments.

Our functional genomic experiments focus on GPCR signaling pathways in ESC-derived cardiac myocytes. We use high-throughput gene inactivation methods (siRNA and gene trapping) in ESCs, then analyze ESC-derived cardiomyocytes. We are also studying ESC differentiation at the level of gene transcription and alternative splicing that guide cell transition from ESCs to myocytes.  We are involved in BayGenomics, a large-scale, academic collaboration with the goal of inactivating all genes in murine ESCs (www.genetrap.org). The power of this approach is highlighted by a recently study in my laboratory that showed that genetic alterations (AKAP-10 trap) in ESC-derived cardiac myocytes alter the electrical responses to hormones (e.g. acetylcholine) and the phenotype was reproduced in mice derived from these ESCs. Furthermore these studies have allowed us to identify a common genetic variation in AKAP-10 that appears to control basal heart rate, a known risk factor for sudden cardiac death. We will continue to focus on studies that have synergy between ESC biology, mouse genetics and human genetics.

We have also engineered GPCRs called RASSLs (receptors activated by small synthetic ligands) that are unresponsive to endogenous natural hormones, but can still be activated by synthetic small-molecule drugs. These RASSLs are powerful probes to examine GPCR signaling in complex systems, including stem cell-derived tissues.  We are the lead laboratory in the world for RASSL use and development. We recently hosted an international meeting bringing RASSL users together for the first time. By combining pathway-oriented bioinformatics with high-throughput experimental methods, and RASSLs that probe these pathways, we are gradually gaining insights into how GPCR signaling can control a wide variety of in vivo responses.