Recent studies have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis, and can be triggered by various physiological and pathological stimuli. The mechanisms by which these proapoptotic stimuli activate germ cell apoptosis are not well understood. The principal intracellular effectors of apoptosis are a family of cysteine proteases called caspases. These enzymes participate in a cascade involving initiator and executioner caspases that is triggered in response to proapoptotic signals. Active executioner caspases are then involved in the cleavage of key cellular proteins, resulting in eventual cell death.
Four specific aims are proposed.
Specific Aim 1 will focus on the characterization of the key molecular components of the intrinsic and extrinsic death pathways leading to caspase activation and increased germ cell apoptosis triggered by deprivation of the gonadotropic support or by mildly increased scrotal temperature.
In Specific Aim 2, we will determine whether inhibition of germ cell apoptosis by replacement therapy of human FSH and/or LH, in the hormone deprivation model, will reverse the apoptosis related changes in the gene expression.
Specific Aim 3 of this proposal will address the role of in vivo pre-treatments of rats with a broad-spectrum caspase inhibitor or a selective inhibitor of caspase 3 like proteases in preventing or attenuating the increased germ cell apoptosis induced by the hormonal and non-hormonal regulatory stimuli.
Specific Aim 4 will focus on further characterization of the role of some of the key upstream modulators (p53, Bcl-2, Fas, and Fas L) of caspase activation in directing germ cell fate using mice harboring null mutation of either p53 or Bcl-2, or mice lacking functional Fas (lpr[cg]) or Fas L (gld). Results of these studies will provide insight into the basic control mechanisms of spermatogenesis in normal and pathological states and will be applicable to the assessment and management of male factor infertility as well as more targeted approaches to male contraception.
|Guo, Jian; Jia, Yue; Tao, Shi-Xin et al. (2009) Expression of nitric oxide synthase during germ cell apoptosis in testis of cynomolgus monkey after testosterone and heat treatment. J Androl 30:190-9|
|Jia, Yue; Castellanos, Jesse; Wang, Christina et al. (2009) Mitogen-activated protein kinase signaling in male germ cell apoptosis in the rat. Biol Reprod 80:771-80|
|Johnson, Candace; Jia, Yue; Wang, Christina et al. (2008) Role of caspase 2 in apoptotic signaling in primate and murine germ cells. Biol Reprod 79:806-14|
|Tsui, Shanli; Naik, Vibha; Hoa, Neil et al. (2008) Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves'disease. J Immunol 181:4397-405|
|Jia, Yue; Hikim, Amiya P Sinha; Lue, Yan-He et al. (2007) Signaling pathways for germ cell death in adult cynomolgus monkeys (Macaca fascicularis) induced by mild testicular hyperthermia and exogenous testosterone treatment. Biol Reprod 77:83-92|
|Zhang, Xue-Sen; Zhang, Zhi-Hong; Jin, Xuan et al. (2006) Dedifferentiation of adult monkey Sertoli cells through activation of extracellularly regulated kinase 1/2 induced by heat treatment. Endocrinology 147:1237-45|
|Vera, Yanira; Erkkila, Krista; Wang, Christina et al. (2006) Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation. Mol Endocrinol 20:1597-609|
|Mahapatra, Nitish R; O'Connor, Daniel T; Vaingankar, Sucheta M et al. (2005) Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 115:1942-52|
|Hikim, Amiya P Sinha; Vera, Yanira; Elhag, Rashid I et al. (2005) Mouse model of male germ cell apoptosis in response to a lack of hormonal stimulation. Indian J Exp Biol 43:1048-57|
|Castanares, Mark; Vera, Yanira; Erkkila, Krista et al. (2005) Minocycline up-regulates BCL-2 levels in mitochondria and attenuates male germ cell apoptosis. Biochem Biophys Res Commun 337:663-9|
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