Testicular torsion is a medical emergency which can cause permanent loss of spermatogenesis. The lesion occurs most commonly in adolescent and pre-adolescent males, and it is acknowledged that the torsion must be diagnosed and treated promptly to avoid the loss of function of the affected testis. Previous studies of the vascular and cellular responses to testicular torsion in the rat model have indicated three separate but related mechanisms of tissue injury. Altered microvascular blood flow, production of intratesticular torsion reactive oxygen species, and induction of germ-cell apoptosis.
The specific aims i n this application will test the overall hypothesis that these three are related in the development of testicular pathology. The testis become ischemic during torsion, but microvascular flow patterns do not return to normal after relief of torsion. We propose to determine the role of neural and non-neural vasoregulation in this alteration. Reperfusion after an ischemic period causes the release of reactive oxygen species (ROS) in other tissues, and ROS can damage cell membranes through lipid peroxidation or can stimulate apoptosis, among other effects. We propose to determine if ROS play a role in the mechanism of the tissue injury seen after relief of testicular torsion, and we propose to determine if ROS induce apoptosis in germ cells. Preliminary evidence indicates that torsion does induce apoptosis specifically in germ cells. We not only propose to determine if the mechanism initiating apoptosis involves ROS, but we propose to partially dissect the molecular pathway to the apoptosis induced by torsion. We will identify key molecules in the germ cell apoptotic pathway by utilizing a gene knock-out strategy in mice. Such an approach utilizes strains of mice lacking the gene for specific proteins in the apoptotic pathway. The germ cell reaction to torsion in these strains will tell whether or not the particular protein under study is important in the pathway. Our studies of both ROS and apoptotic pathway proteins have potential to lead to improved therapies for human patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG4-UROL (01))
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Mullins, Christopher V
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University of Virginia
Schools of Medicine
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Lysiak, Jeffrey J; Kirby, Jennifer L; Tremblay, Jacques J et al. (2009) Hypoxia-inducible factor-1alpha is constitutively expressed in murine Leydig cells and regulates 3beta-hydroxysteroid dehydrogenase type 1 promoter activity. J Androl 30:146-56
Lysiak, Jeffrey J; Zheng, Shuqiu; Woodson, Robin et al. (2007) Caspase-9-dependent pathway to murine germ cell apoptosis: mediation by oxidative stress, BAX, and caspase 2. Cell Tissue Res 328:411-9
Turner, Terry T; Lysiak, Jeffrey J; Shannon, John D et al. (2006) Testicular torsion alters the presence of specific proteins in the mouse testis as well as the phosphorylation status of specific proteins. J Androl 27:285-93
Turner, T T; Johnston, D S; Jelinsky, S A (2006) Epididymal genomics and the search for a male contraceptive. Mol Cell Endocrinol 250:178-83
Zheng, Shuqiu; Turner, Terry T; Lysiak, Jeffrey J (2006) Caspase 2 activity contributes to the initial wave of germ cell apoptosis during the first round of spermatogenesis. Biol Reprod 74:1026-33
Yang, Sang-Kuk; Attipoe, Sharon; Klausner, Adam P et al. (2006) In vivo detection of apoptotic cells in the testis using fluorescence labeled annexin V in a mouse model of testicular torsion. J Urol 176:830-5
Turner, Terry T; Bang, Hyun J; Lysiak, Jeffrey J (2005) Experimental testicular torsion: reperfusion blood flow and subsequent testicular venous plasma testosterone concentrations. Urology 65:390-4
Lysiak, Jeffrey J; Bang, Hyun J; Nguyen, Quoc An T et al. (2005) Activation of the nuclear factor kappa B pathway following ischemia-reperfusion of the murine testis. J Androl 26:129-35
Turner, Terry T; Bang, Hyun J; Lysiak, Jeffery L (2004) The molecular pathology of experimental testicular torsion suggests adjunct therapy to surgical repair. J Urol 172:2574-8
Lysiak, Jeffrey J; Nguyen, Quoc An T; Kirby, Jennifer L et al. (2003) Ischemia-reperfusion of the murine testis stimulates the expression of proinflammatory cytokines and activation of c-jun N-terminal kinase in a pathway to E-selectin expression. Biol Reprod 69:202-10

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