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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064679-05
Application #
7235390
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Rankin, Tracy L
Project Start
2003-08-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$320,597
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Sezen, Sena F; Lagoda, Gwen; Burnett, Arthur L (2009) Role of immunophilins in recovery of erectile function after cavernous nerve injury. J Sex Med 6 Suppl 3:340-6
Lagoda, Gwen; Sezen, Sena F; Burnett, Arthur L (2009) FK506 and rapamycin neuroprotect erection and involve different immunophilins in a rat model of cavernous nerve injury. J Sex Med 6:1914-23
Lagoda, Gwen; Sezen, Sena F; Liu, Tongyun et al. (2008) FK506-binding protein localizations in human penile innervation. BJU Int 101:604-9
Valentine, Heather; Chen, Yi; Guo, Hongzhi et al. (2007) Neuroimmunophilin ligands protect cavernous nerves after crush injury in the rat: new experimental paradigms. Eur Urol 51:1724-31
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Allaf, Mohamad E; Hoke, Ahmet; Burnett, Arthur L (2005) Erythropoietin promotes the recovery of erectile function following cavernous nerve injury. J Urol 174:2060-4