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: 6874405
• 负责人: JAMES K TSURUTA
• 金额: $ 23万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874405
• 关键词: DNA binding protein; RNase protection assay; Sertoli cells; activins; biological signal transduction; cell growth regulation; cell proliferation; contraceptives; cyclin dependent kinase; enzyme inhibitors; follistatin; genetic transcription; hormone receptor; inhibin; laboratory rat; northern blottings; nucleic acid purification; paracrine; protein biosynthesis; retinoids; sperm; testis; vitamin A deficiency

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）：本项目的广泛、长期目标是基于维生素A缺乏（VAD）睾丸中精原细胞（Spg）可逆性阻滞的避孕策略的合理设计。我们的目的是揭示在这个模型中可逆地阻止Spg的具体机制。在VAD睾丸上皮中的两种相关细胞类型（停滞的Spg和Sertoli细胞）中，只有Sertoli细胞表达大量的视黄酸受体α（RAR α）。因此，我们的总体假设：支持细胞的旁分泌信号介导维生素A对Spg的影响。我们的工作假设是，支持细胞来源的激活素逮捕Spg在VAD睾丸和维生素A救援通过下调激活素和上调其结合蛋白卵泡抑素样蛋白的增殖。这一初始资助期的目标是通过确定特定信号分子和途径在维生素A依赖性调节Spg增殖期间发挥的作用来确定未来的避孕目标。我们打算通过完成以下具体目标来实现这一目标：（1）测试我们的预测，即维生素A调节特定的信号传导因子（激活素，卵泡抑素），结合蛋白（卵泡抑素，卵泡抑素相关蛋白）和受体（激活素受体i和ii）。(2)确定睾丸的维生素a状态是否调节激活素受体下游的smad依赖性信号通路和细胞周期蛋白依赖性激酶抑制剂的合成，从而影响精原细胞周期的变化。(3)测试候选因子调节Spg增殖的功效，并测试我们的假设，即激活素依赖性信号调节细胞周期蛋白依赖性激酶抑制剂来影响这些变化。(4)鉴定参与精原细胞可逆性VAD阻滞的其他旁分泌因子和受体。完成这些目标将定义特定机制，逆转指导精原细胞增殖的遗传程序中的内在检查点，这是我们设计成功男性避孕药目标的重大进展。