Project Summary/Abstract: The PI is the Alan MacDiarmid Term Professor of Chemistry at the University of Pennsylvania (UPenn), where in 2003 he launched a multidisciplinary research program developing molecular probes that have led to breakthroughs in Chemical Biology, Radiology, Cellular Genomics/Transcriptomics, and Anesthesiology. In the course of this research, the PI has mentored 9 postdoctoral fellows, 35 graduate students, and 50 undergraduates, with many winning national awards and most graduates pursuing careers in science and biomedicine. The PI's research draws on formal training in supramolecular organic chemistry (Harvard-Mainz), bioinorganic and biophysical chemistry (Caltech, Ph.D.), and biology/biomolecular imaging (Caltech, postdoc). The PI's immersion for the past 19 years in the biomedical research enterprise at UPenn has burnished this experience. Through key collaborations, the PI has tackled significant biomedical research questions, using the tools of chemical synthesis, protein and oligonucleotide chemistry, and bioanalytical chemistry. The PI's 105 peer-reviewed publications, 7 patents, 4 edited books and contributed book chapters highlight a track record of productivity, innovation, impact, and dissemination in the development and application of chemical tools for biomedical research. The PI's service, including current membership on the SBCA study section, confirms a strong commitment to scientific review, education, outreach, community building, and junior faculty mentoring. This MIRA award extends the PI's highly successful GM-funded research in three program areas: 1) molecular imaging using xenon- based MRI contrast agents; 2) cellular transcriptome-in-vivo-analysis and mRNA regulation using light-activated oligonucleotide probes; and, 3) elucidation of general anesthetic-protein interactions with novel fluorescent probes, ultrasensitive 129Xe NMR spectroscopy, and other biophysical methods. Significant goals of the next five-year period are to refine these probe- based technologies with world-class research-collaborators at UPenn and establish high-value probes that can be disseminated broadly to the biomedical research community. Collectively, these tools will advance our molecular understanding of normal biological/biomedical processes (including general anesthesia), and provide avenues for improved diagnosis and treatment of many human diseases, including cancer, neurodegeneration, and diabetes.