GROWTH FACTOR SIGNAL TRANSDUCTION AND SPERMATOGENESIS

描述：(改编自申请人的摘要)作为生长因子， 细胞因子是已知的正常细胞增殖和异常细胞的媒介。 造血和免疫系统中的循环相关反应。缺陷 以及体内特定细胞因子的不适当表达与 与精子发生的中断有关。这些发现暗示了他们的 在男性生殖细胞谱系中的促增殖和抗增殖作用。 多种细胞因子和生长因子的生物学活性被介导 通过同源受体和特异性受体相关蛋白(JAK)。 不同的蛋白质-蛋白质相互作用对这些信号至关重要 通过一个家族诱导基因表达的转导事件 被称为STAT蛋白的潜在转录因子。最近的研究表明 鉴定了JAK酪氨酸激酶和细胞因子/生长的几个成员 特定雄性生殖细胞中的因子受体。工作假说是一个 关键增长因素水平之间的不平衡可能是由于 恶劣的环境。据认为，这种细胞外刺激可以 在受体阳性的发育中生殖细胞内产生不适当的信号 在他们的两个激酶通路(JAK和MAPK)的水平上。三个具体的 为了检验PI的工作假说，提出了AIMS。(1)描述 这些生长因子对生殖细胞DNA合成和细胞周期的影响 视黄酸受体相互作用的研究进展 以及细胞因子信号对细胞增殖的影响。(2)确立委员会的角色 SOCS家族的细胞因子诱导的抑制物，并确定其作用 STAT功能中的细胞内区划。(3)刻画 IL-6和MAPK信号在生殖细胞增殖和TO中的相互作用 测试暴露在炎症或环境毒物中的生殖细胞是否可以 通过生长因子/细胞因子拯救从细胞凋亡中拯救出来。它是圆周率的长 学期目标包括确定新的治疗部位 预防感染期间生殖细胞发育中断的干预措施， 炎症和基于细胞因子的男性不育。

DESCRIPTION: (Adapted from the applicant's abstract) 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.