Recently published work has shown that the immunophilin ligand FK506 potently protects penile innervation from degeneration and preserves penile erection after cavernous nerve crush injury in a rat model. This work has coincided with recent investigations in other neurobiologic research fields which have shown immunophilins are abundantly contained in the nervous system and they assume important roles in multiple areas of neural function, such as neuroprotection, mediation of neurotrophic influences, and neurotransmitter release. The exact molecular mechanisms exerted by immunophilin ligands that preserve erectile function remain unknown. Elucidation of such mechanisms may afford additional unique insights into the functional roles of immunophilins and define new pharmacologic targets for treating erectile dysfunction associated with neurogenic disorders. The importance of developing new strategies for treating erectile dysfunction is understandable when considering that the condition is recognized to affect 10 to 20% of the American male population and carry enormous quality of life ramifications and associations with other health co-morbidities. The research proposal centers on two primary research areas, the molecular mechanisms associated with the functional neurotrophic effects of immunophilins and their respective ligands in reference to penile nerve function, and the action of immunophilin ligands with non-immunosuppressant features in promoting erectile function recovery after cavernous nerve injury. Specific aims are: (1) to characterize the immunophilin receptor proteins and their signaling pathways respectively mediating neuroprotection and neuroregeneration in the penis; (2) to distinguish the neurotrophic effects of calcineurin-dependent (immunosuppressant) immunophilin ligands and calcineurin-independent (non-immunosuppressant) immunophilin ligands on erectile function after cavernous nerve injury; (3) to evaluate the role of neuronal nitric oxide synthase in the neurotrophic actions of immunophilins in the penis after cavernous nerve injury; and (4) to evaluate the influence of immunophilins on the neurotrophic actions of neurotrophins in the penis after cavernous nerve injury. The experimental work described herein combines molecular biologic, erection physiologic, and morphologic studies.