This funding opportunity announcement (FOA) is designed to support highly integrated research teams of three to six PD/PIs to address ambitious and challenging research questions that are important for the mission of NIGMS and are beyond the scope of one or two investigators. The project goals should not be achievable with a collection of individual efforts or projects. Teams are encouraged to consider far-reaching objectives that will produce major advances in their fields. • The FOA is being reissued to allow submission of applications that include NIH defined clinical trials. • NIGMS will not accept clinical trials that are designed to test safety and efficacy of interventions (Phase I, Phase II, Phase III) for the purpose of future clinical treatment and/or regulatory approval in response to this FOA. • Applications that are mainly focused on the creation, expansion, and/or maintenance of community resources, creation of new technologies or infrastructure development are not appropriate for this FOA.