GROWTH FACTOR SIGNAL TRANSDUCTION AND SPERMATOGENESIS

生长因子信号传导和精子发生

• 批准号: 6637398
• 负责人: PATRICIA L. MORRIS
• 金额: $ 29.49万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-26 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637398
• 关键词: DNA replication; JAK kinase; biological signal transduction; cell cycle; clinical research; growth factor; human subject; interleukin 6; laboratory mouse; male; mitogen activated protein kinase; nuclear receptors; retinoid binding proteins; spermatogenesis; transcription factor

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.

描述：（根据申请人的摘要改编）作为增长因素， 细胞因子是正常增殖和异常细胞的已知介质 造血和免疫系统中与周期相关的反应。缺陷 体内特定细胞因子的不当表达与 精子发生中的破坏。这些发现暗示了他们 在男性生殖细胞谱系中促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介导的 通过相关受体和特定受体相关激酶（JAK）。 独特的蛋白质 - 蛋白质相互作用对于这些信号至关重要 转导事件导致通过家族诱导基因表达 被称为Stat蛋白的潜在转录因子。最近的研究 确定了Jak酪氨酸激酶和细胞因子/生长的几个成员 特定男性生殖细胞中的因子受体。有效的假设是 关键增长因素水平之间的不平衡可能是由 敌对的环境。有人提出这种额外的细胞刺激可以 在受体阳性发育中的生殖细胞中产生不适当的信号 在他们的两个激酶途径（JAK和MAPK）的水平上。三个具体 提出了目的来检验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 细胞增殖上的细胞因子信号传导。 （2）确定 SOCS细胞因子诱导抑制剂的家族，并确定 STAT功能中的细胞内隔室化。 （3）表征 在生殖细胞增殖中IL6和MAPK信号传导之间的串扰，到 测试暴露于炎症或环境有毒物质的生殖细胞是否可以 通过生长因子/细胞因子救援从凋亡中救出。这是Pi的长期 定期目标，包括识别用于治疗的新颖地点 干预以防止感染过程中生殖细胞发育的破坏， 炎症和基于细胞因子的男性不育症。