GROWTH FACTOR SIGNAL TRANSDUCTION AND SPERMATOGENESIS

描述：（改编自申请人摘要）作为生长因子， 细胞因子是已知的正常增殖和异常细胞增殖的介质， 造血和免疫系统中的周期相关反应。缺陷 以及体内特异性细胞因子的不适当表达与 精子发生中断这些发现表明， 在雄性生殖细胞谱系中的促增殖和抗增殖作用中的作用。 多种细胞因子和生长因子的生物学活性是由 通过同源受体和特异性受体相关激酶（JAK）。 不同的蛋白质-蛋白质相互作用对于这些信号至关重要。 导致通过家族诱导基因表达的转导事件 称为STAT蛋白的潜在转录因子。最近的研究 鉴定了JAK酪氨酸激酶和细胞因子/生长因子的几个成员， 特定雄性生殖细胞中的因子受体。工作假设是， 关键生长因子水平之间的不平衡可能是由于 恶劣的环境。有人提出，这种细胞外刺激可以 在受体阳性的发育中的生殖细胞内产生不适当的信号 在其两种激酶途径（JAK和MAPK）的水平上。三个具体 目的是提出测试PI的工作假设。(1)表征 这些生长因子对生殖细胞DNA合成和细胞周期的影响 进展，并确定视黄酸受体的相互作用 和细胞因子信号对细胞增殖的影响。(2)为了确立 SOCS家族的精氨酸诱导的抑制剂，并确定的作用 STAT功能的细胞内区室化。(3)表征 生殖细胞增殖中IL 6和MAPK信号传导之间的相互作用， 测试暴露于炎症或环境毒物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。这是PI的长 术语目标包括确定新的治疗部位 干预以防止感染期间生殖细胞发育受到破坏， 炎症和基于精氨酸的男性不育症。

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.