Reversible vitamin A-dependent arrest of spermatogonia

可逆的维生素 A 依赖性精原细胞停滞

• 批准号: 7228881
• 负责人: JAMES K TSURUTA
• 金额: $ 21.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228881
• 关键词: Activin Receptor; Activins; Binding Proteins; Cell Cycle; Contraceptive Agents; Cyclin-Dependent Kinase Inhibitor; Epithelium; Follistatin; Follistatin-Like Protein 3; Follistatin-Related Proteins; Funding; Future; Genetic Programming; Goals; Male Contraceptive Agents; Mediating; Modeling; Paracrine Communication; Pathway interactions; Play; Proteins; Range; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Spermatogonia; Testing; Testis; Vitamin A; Vitamins; Work; base; cell type; contraceptive target; design; inhibin; inhibin receptor; paracrine; receptor; retinoic acid receptor alpha; sertoli cell

DESCRIPTION (provided by applicant): The broad, long-range objective of this project is the rational design of contraceptive strategies based on the reversible arrest of spermatogonia (Spg) in the vitamin A-deficient (VAD) testis. Our intent is to uncover specific mechanisms that reversibly arrest Spg in this model. Of the two pertinent cell types (arrested Spg and Sertoli cells) in the epithelium of the VAD testis, only the Sertoli cell expresses significant amounts of retinoic acid receptor-alpha (RARalpha). Thus, our overall hypothesis: paracrine signal(s) from Sertoli cells mediate the effects of vitamin A on Spg. Our working hypothesis is that Sertoli cell-derived activin arrests Spg in the VAD testis and that vitamin A rescues proliferation by down-regulating activin and up-regulating its binding protein follistatin-like protein. The objectives of this initial funding period are to identify future contraceptive targets by determining the role specific signaling molecules and pathways play during the vitamin A-dependent regulation of Spg proliferation. We intend to accomplish this by completing the following specific aims: (1) Test our prediction that vitamin A regulates specific signaling factors (activin, inhibin), binding proteins (follistatin, follistatin-related protein) and receptors (activin receptors i & ii). (2) Determine whether the vitamin a status of the testis regulates smad-dependent signaling pathways downstream of the activin receptor and synthesis of cyclin-dependent kinase inhibitor(s) to effect changes in the spermatogonial cell cycle. (3) Test the efficacy of candidate factors to regulate the proliferation of Spg and test our hypothesis that activin-dependent signaling regulates cyclin-dependent kinase inhibitors to effect these changes. (4) Identify additional paracrine factors and receptors that participate in the reversible VAD arrest of spermatogonia. Completing these aims will define specific mechanisms that reverse an intrinsic checkpoint in the genetic program directing spermatogonial proliferation, a significant advance towards our goal of designing a successful male contraceptive.

描述（由申请人提供）：该项目的广泛，远程目标是基于维生素A缺陷型（VAD）睾丸的精子（SPG）的可逆性逮捕的避孕策略的合理设计。我们的目的是发现在此模型中可逆地阻止SPG的特定机制。在VAD睾丸上皮的两种相关细胞类型（被捕的SPG和Sertoli细胞）中，只有Sertoli细胞表达大量的视黄酸受体-Alpha（Raralpha）。因此，我们的总体假设：Sertoli细胞的旁分泌信号介导了维生素A对SPG的影响。我们的工作假设是，Sertoli细胞衍生的激活素在VAD睾丸中阻止了SPG，并且维生素A通过下调激活素并上调其结合蛋白卵泡蛋白样蛋白来挽救增殖。该初始资金期间的目标是通过确定在SPG增殖的维生素A依赖性调节过程中发挥特定的信号分子和途径来确定未来的避孕目标。我们打算通过完成以下特定目的来实现这一目标：（1）测试我们的预测维生素A调节特定的信号因子（激活素，抑制素），结合蛋白（Follistatin，Follistatin，Follistatin相关蛋白）和受体（激活素受体I和II）。 （2）确定睾丸的维生素A状态是否调节了激活素受体下游的SMAD依赖性信号通路，并调节细胞周期蛋白依赖性激酶抑制剂的合成以影响精子细胞周期的变化。 （3）测试候选因素调节SPG增殖的功效并检验我们的假设，即激活素依赖性信号传导调节细胞周期蛋白依赖性激酶抑制剂以实现这些变化。 （4）确定参与精子可逆的VAD停滞的其他旁分泌因子和受体。完成这些目标将定义特定的机制，这些机制在指导精子增生的基因程序中扭转了内在检查点，这是我们设计成功的男性避孕药的重大进步。