As growth factors, cytokines are known mediators of both normal proliferation and aberrant cell cycle-related responses in the hematopoietic and immune systems. Deficiencies as well as inappropriate expression of specific cytokines in vivo is associated with disruptions in spermatogenesis. These findings are suggestive of their role in pro- and anti-proliferative effects within the male germ cell lineage. The biological activities of multiple cytokines and growth factors are mediated through cognate receptors and specific receptor-associated kinases (JAK). Distinct protein-protein interactions are critical for these signal transduction events leading to an induction of gene expression through a family of latent transcription factors called STAT proteins. Recent studies have identified several members of the JAK tyrosine kinases and cytokine/growth factor receptors in specific male germ cells. The working hypothesis is that an imbalance between the levels of critical growth factors can result from a hostile environment. It is proposed that such extra cellular stimuli can generate inappropriate signals within receptor-positive developing germ cells at the level of two of their kinase pathways (JAK and MAPK).
Three specific aims are proposed to test the PI's working hypothesis. (1) To characterize the effects of these growth factors on germ cell DNA synthesis and cell cycle progression and, to determine the interactions of the retinoic acid receptors and cytokine signaling on cell proliferation. (2) To establish the role of the SOCS family of cytokine-inducible inhibitors and, determine the role of intracellular compartmentalization in STAT function. (3) To characterize the cross-talk between IL6 and MAPK signaling in germ cell proliferation and, to test whether germ cells exposed to inflammation or environmental toxicants can be rescued from apoptosis by growth factor/cytokine rescue. It is the PI's long term goals to include the identification of novel sites for therapeutic intervention to prevent disruption of germ cell development during infection, inflammation and in cytokine-based male infertility.
