ABSTRACT This newly established Core D aims to advance novel small-molecule therapies for gastrointestinal, renal, endocrine and pulmonary manifestations of CF with the potential for translation into the clinic. To achieve this objective, Core D carries out microsomal stability, animal pharmacology, efficacy and preliminary toxicity studies to characterize and prioritize drug candidates that are identified in Cores A and B, and optimized in Core C. Core D also provides essential resources and expertise to advance research on CF organ manifestations and drug discovery that include establishing experimental animal models of CF disease, and providing transgenic mice. The proposed functions of Core D have been carried out successfully in multiple projects during the current award period, and formally establishing Core D will enable performance of these functions in a more efficient and organized manner. Important areas of investigation to be facilitated by Core D include CF constipation and related disorders (meconium ileus and distal intestinal obstruction syndrome), CF- related enteric hyperoxaluria and nephrolithiasis, CF-related diabetes mellitus and lung infections and inflammation. Core D will perform key animal experiments to test epithelial ion transport modulators discovered by the CF Core Center, which has a track record of identifying novel therapeutic candidates for CF manifestations, and generating intellectual property leading to clinical development.