TRD4 Project Summary The broad mission of our Center for Advanced Imaging Innovation and Research (CAI2R) is to bring together collaborative translational research teams for the development of high-impact biomedical imaging technologies, with the ultimate goal of changing day-to-day clinical practice. With the other three Technology Research and development (TR&D) Projects in our Center focused on generating rich, quantitative data streams, a key question remains: What do these data streams really mean at the level of tissue function? Answering such a question requires bridging spatial scales from the macroscopic (millimeter) dimensions of image voxels to the mesoscopic (micrometer) dimensions of cells, where many disease processes originate. An ability to map cellular-level biophysical parameters would open new productive avenues for both clinical applications and basic research. In TR&D Project 4, we will integrate tissue microstructure mapping into comprehensive image acquisitions, to achieve specificity to tissue changes at the cellular level, for understanding physiology and pathology, for earliest disease detection, for monitoring of disease progression, and for quantification of treatment efficacy. The overarching goal of this project is to transform MRI from an imaging device to an accurate and precise scientific instrument for measuring microstructural tissue parameters. Our Specific Aims are 1) To establish the underlying biophysical information content of MRI data, using methods from mesoscopic physics; 2) To develop and validate biophysical models for the microstructure of brain, muscle, and cancer tissues, which may be used to convert image data to microstructural maps in patients with neurological, musculoskeletal, or oncologic disorders; and 3) To translate these modeling and mapping approaches into clinical practice.