Many disorders of the lower urogenital tract involve one or more aspects of microvessel failure. Examples of specific disorders include: cryptorchidism, impotence, inflammatory disturbances (i.e. cystitis, orchitis, prostatitis), torsion, and varicocele. I hypothesize that the primary cause for these disturbances involves a decline or loss in vascular function that precedes clinical signs of organ failure. This proposition is supported by a massive body of indirect evidence derived from biochemical, physiological and pathological studies of genitourinary structures in healthy and diseased states. I propose to use the hamster testis as a model to test this hypothesis because its exterior location is particularly well suited for the direct observation of all classes of microvessels by intravital microscopy. Furthermore, the functions of the two parenchymal cell types (Leydig cells = steroidogenesis, tubular Sertoli/germ cells = spermatogenesis) can be assessed independently and simultaneously with indices of vascular perfusion. The vasomotor control of arteriolar tone and capillary perfusion will be manipulated experimentally by: i) electrical stimulation of the spermatic nerve, ii) limiting perfusion pressure or flow in the spermatic artery, and iii) torsion and detorsion of the spermatic cord to provoke ischemia/reperfusion injury. Each form of vasomotor control will be assessed concurrently with parenchymal cell performance to uncover the vascular mechanisms that limit or control the availability of oxygen, tropic hormones, and substrates for steroidogenesis or spermatogenesis. Another objective of these experiments is to combine mapetic resonance imaging techniques with intravital assessments of capillary perfusion and cell performance. The methodologies will be used in parallel experiments to test the feasibility of developing noninvasive methods to estimate both testicular perfusion and the function of Leydig, Sertoli, and/or germ cells during the cycle of the seminiferous epithelium. The results of magnetic resonance perfusion imaging and magnetic resonance spectroscopy provide the potential for developing new clinical procedures to facillitate the diagnosis and improve the medical management of microvessel failure in the human testicle. All of the investigative approaches proposed in this application are expected to offer new insights about the proximate causes of the loss or reduction in testicular function following torsion of the spermatic cord. The experimental strategies are unique in their capacity to develop important new approaches to assess the cellular and molecular basis of vascular failure common to many genitourinary disorders. To my knowledge, no other laboratory possesses the background and skills to integrate intravital and magnetic resonance techniques to """"""""look"""""""" inside the testis and assess cell function in situ.
| Billups, K L; Sherley, J L; Palladino, M A et al. (1995) Evidence for E-selectin complement regulatory domain mRNA splice variants in the rat. J Lab Clin Med 126:580-7 |
| Billups, K L; Palladino, M A; Hinton, B T et al. (1995) Expression of E-selectin mRNA during ischemia/reperfusion injury. J Lab Clin Med 125:626-33 |
