Project Title: Rationally Designed, Target-specific Imaging Probes for Nephro-urology Diagnoses Project Summary The project focuses on novel design and testing of kidney-specific probes for radionuclide renal imaging. Unlike existing standard-of-care tracers used in the clinic that rely on passive uptake and clearance mechanisms, our recombinant probes are based on targeted design for mapping kidney functions, including filtration at the glomerulus and protein sorting at the proximal tubule. This approach enables functional renal imaging with molecular specificity. We adapted a fusion strategy in designing the probes, in which we joined modular segments of selected plasma proteins to form new hybrid probes. These modular segments are the functional units that can individually interact with their cognate renal receptors. Accordingly, it is anticipated that each probe will follow a guided intrarenal passage and sequentially interactions with intended receptors. This novel approach holds promise, as demonstrated in proof-of-concept studies and will continue to be pursued, for measuring distinct functions of the kidney. We will accomplish our research goal via three interconnected and synergistic Specific Aims, which are designed for measuring critical aspects of the renal function and pathophysiology, including glomerular filtration and tubular reuptake (Aim 1), glomerular density (Aim 2), and the early pathological changes in the filtration barrier (Aim 3). The studies will be conducted in acute and chronic settings as appropriate using relevant kidney disease models such as ischemic/reperfusion injury, nephrotoxicity, hypertension and autoimmunity, which are representative of common renal diseases in humans. Overall, our new probes are intended for directly addressing the needs for early and specific markers of renal diseases. The imaging data from these probes will provide important mechanistic insights for advancing the technologies toward their ultimate translation to patient care.

PROJECT NARRATIVE Following a recombinant design approach, we will develop and characterize a series of kidney- specific radionuclide imaging probes for targeting the structures and functions of the kidney. The proposed studies are designed to accomplish our research goal of assessing renal pathophysiology in diseases in a minimally invasive fashion with molecular specificity.