ALCOHOL & RETINOID SIGNALING IN TESTIS DEVELOPMENT

描述：(改编自《调查者摘要》)： 酒精在胚胎发育过程中是众所周知的。器官系统受到影响 受酒精影响的是男性生殖系统。有报道称， 产生睾丸激素和不正常的精子产生。不同的机制有 被提议用来解释酒精的毒性影响。一种机制是 酒精对维甲酸代谢的影响导致视黄醇信号的改变 以及维甲酸受体的功能。建议的研究是设计的 为了更好地了解酒精可能通过的细胞信号机制 影响维甲酸受体，维甲酸受体是睾丸发育所必需的 和精子发生。需要检验的假设是，产前和早期 出生后酒精暴露不适当地改变了视黄醇信号，这 是睾丸异常增殖的部分原因，并可能导致 精子产量降低。PI的研究表明，维甲酸增加了 睾丸细胞中转化生长因子β水平升高，细胞增殖增加。自.以来 转化生长因子-B(转化生长因子-β)已被证明可降低睾酮 在胎儿睾丸细胞中的水平，维甲酸，类似于酒精，具有 有可能减少睾丸素的产生。即使是短暂的变化 在胎儿和新生儿时期的关键时刻的睾酮水平会产生 由于支持细胞对成人精子输出的长期影响 增殖只发生在睾丸发育的早期。研究设计 包括以下具体目标。《特定目标#1》考察了 酒精对睾丸增殖的影响维甲酸受体的表达 TGFb的产生，以及维甲酸和成人精子的输出。特定目标 #2研究了维甲酸受体在调节血管紧张素转换酶的作用 酒精对胚胎和新生儿睾丸发育的影响。具体目标#3 研究酒精影响维甲酸的分子信号通路。 酸受体信号。少年派将使用新颖的胚胎和早期出生 混合睾丸培养在我们的初步研究中被证明是非常有用的 以及怀孕的老鼠。酒精的剂量和发育特异性影响 在这些睾丸培养物和怀孕大鼠的胚胎上 调查过了。这些具体目标的完成将提供对 将对怀孕大鼠的胎儿进行调查。完成这些具体工作 AIMS将提供对酒精在 并建立了酒精在睾丸中作用的分子模型。 PI将显示酒精不适当地改变了维甲酸的活性 酸受体，然后改变维甲酸代谢，这导致 睾丸细胞增殖的改变。更好地理解 酒精的作用机制可能导致新的药物设计来帮助患者 母亲酗酒。

DESCRIPTION: (Adapted from the Investigator's Abstract): Teratogenic effects of alcohol during embryonic development are well known. An organ system influenced by alcohol is male reproductive system. There are reports of decreased testosterone production and subnormal sperm production. Diverse mechanisms have been proposed to account for the toxic effects of alcohol. One mechanism is altered retinoid signaling due to alcohol's influence on retinoid metabolism and the function of retinoic acid receptors. The proposed research is designed to better understand the cellular signaling mechanisms by which alcohol may affect retinoic acid receptors, which are essential for testicular development and spermatogenesis. The hypothesis to be tested is that prenatal and early postnatal alcohol exposures inappropriately alter retinoid signaling and, this is partially responsible for abnormal testicular proliferation and may lead to lowered sperm output. The PI's studies demonstrate that retinoic acid increased TGF beta levels in testicular cells and increased cell proliferation. Since transforming growth factor-B (TGF beta) has been shown to decrease testosterone levels in fetal testicular cells, retinoic acid, similar to alcohol, has the potential to decrease testosterone production. Even transient changes in testosterone levels at critical times in fetal and neonatal times can produce long-term effects on sperm output in the adult because Sertoli cell proliferation only occurs in early testicular development. The research design consists of the following specific aims. Specific Aim #1 examines the effect of alcohol on testicular proliferation the expression of retinoic acid receptor, the production of TGFB, and retinoic acid and adult sperm output. Specific Aim #2 examines the role of retinoic acid receptors in mediating the effects of alcohol during embryonic and neonatal testis development. Specific Aim #3 examines the molecular signaling pathways by which alcohol influences retinoic acid receptor signaling. The PI will use novel embryonic and early postnatal mixed testicular cultures proven to be very useful in our preliminary studies as well as pregnant rats. The dose-and developmental-specific impact of alcohol on these testicular cultures and the fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into the when alcohol can have adverse action during testis development and develop a molecular model of alcohol action in testis. The PI will show that alcohol inappropriately alters the activity of retinoic acid receptors and then changes retinoid metabolism, and this leads to alteration in testicular cell proliferation. A better understanding of the mechanism of alcohol action may lead to novel drug design to help victims of maternal alcohol abuse.