PROJECT SUMMARY / ABSTRACT This application is submitted in response to RFA-RM-18-025, which is focused on the development of new technologies to noninvasively label and monitor genome-edited cells in vivo. Our submission meets the objective of the RFA by establishing a new field of total-body positron emission tomography (PET) imaging for somatic cell genome editing, and with quantitative methodologies needed to support translation. This application is grounded in a proven infrastructure of innovative tools, technologies, and resources, and a highly accomplished multidisciplinary team of investigators. Studies will culminate in translational tools for the in vitro design (phantoms, quantitative measures) and in vivo methods for monitoring genome-edited cells that will inform future clinical investigations across organ systems for the treatment of human disease. The UH2 phase will focus on in vitro and in vivo quantitative testing with edited cells in prototype models (Specific Aim 1). The activities in these studies can be adapted to any cell type or organ system. The UH3 phase will address detection efficiency and safety assessments in vivo, including the potential for immune responses in an animal model that employs quantitative imaging analysis and related tools for translation (Specific Aim 2). Overall, these investigations will establish a new field of total-body PET imaging for monitoring the safety and efficiency of somatic cell genome editing and will contribute new knowledge that leads to future well-designed preclinical studies and human clinical trials.