TUMOR NECROSIS FACTOR AND FOLLICLE DEVELOPMENT

拟议研究的总体目标是进一步推动我们的 了解胎儿和新生儿的卵巢发育，以及 特异性地研究肿瘤坏死因子-α(TNF)的作用 在卵泡分化和类固醇生成中起重要作用。最近，肿瘤坏死因子 与卵巢癌的发展有关，但它也有细胞毒性 对其他类型的癌症的效果。希望通过对角色的定义 对肿瘤坏死因子在正常发育中的认识将导致对异常的认识 不孕不育和卵巢癌等状态。这项研究尤其是 重要的是因为涉及肿瘤坏死因子作为抗癌药物的临床试验 已经启动；利用抗肿瘤坏死因子策略的进一步试验已经 是有人建议的。因此，了解肿瘤坏死因子的正常生理作用 已经提出了一些策略。因此，理解常态 肿瘤坏死因子对生殖参数的生理作用是至关重要的。上一首 研究表明，肿瘤坏死因子在大鼠卵母细胞中出现的时间大约是 诞生；因此，第一个具体目标是明确指出 大鼠卵母细胞产生肿瘤坏死因子及其mRNA的时间。第二个目标是 确定两种肿瘤坏死因子亚型中的哪一种存在于胎儿和 新生大鼠卵巢，以确定肿瘤坏死因子是否与 与发育事件有关。第三个具体目标是测试 假设肿瘤坏死因子是正常卵泡分化所必需的。这个 将使用的策略是通过使用肿瘤坏死因子反义来中和肿瘤坏死因子 寡核苷酸在卵巢器官培养体系中的应用及效果观察 体内卵泡分化的研究。最终的具体目标是测试 假设肿瘤坏死因子将显著影响 新生大鼠卵巢的类固醇合成能力。以前的工作都没有 已经阐明了肿瘤坏死因子在新生儿卵巢中的作用；然而，以前 对各种成人卵巢细胞类型的研究表明，肿瘤坏死因子 影响促性腺激素刺激，而不是基础类固醇的产生。 因此，肿瘤坏死因子对基础和促性腺激素刺激的影响 黄体酮和雌二醇的产生将用分散的 卵巢培养系统。建议的研究对指导未来是必不可少的。 卵巢肿瘤坏死因子在围产期的功能研究

The overall objective of the proposed research is to further our understanding of ovarian development in the fetus and neonate, and specifically to investigate the role of tumor necrosis factor-alpha (TNF) in follicle differentiation and steroidogenesis. TNF has recently been implicated in the development of ovarian cancer, yet it also has cytotoxic effects against other types of cancer. It is hoped that defining the role of TNF in normal development will lead to an understanding of abnormal states such as infertility and ovarian cancer. This research is especially important because clinical trials involving TNF as a cancer-fighting agent have been initiated; and further trials utilizing anti-TNF strategies have been suggested. Thus, understanding the normal physiological role of TNF strategies have been suggested. Thus, understanding the normal physiological role of TNF on reproductive parameters is critical. Previous research has shown that TNF appears in rat oocytes around the time of birth; therefore the first specific aim is to specifically pinpoint the time that TNF and its mRNA arise in the rat oocyte. The second aim is to determine which of the two TNF subtypes is present within the fetal and neonatal rat ovary, in an effort to determine whether TNF can be correlated with developmental events. The third specific aim is to test the hypothesis that TNF is necessary for normal follicle differentiation. The strategy that will be used is to neutralize TNF by using TNF antisense oligonucleotides in an ovarian organ culture system and observing effects on follicle differentiation in vivo. The final specific aim is to test the hypothesis that TNF will significantly affect the development of steroidogenic capacity of the neonatal rat ovary. No previous work has been done ot clarify effect of TNF in the neonatal ovary; however, previous studies on various adult ovarian cell types have demonstrated that TNF affects gonadotropin-stimulated, rather than basal steroid production. Therefore, the effect of TNF on basal and gonadotropin-stimulated progesterone and estradiol production will be determined using a dispersed ovary culture system. The proposed studies are essential to direct future studies on the function of ovarian TNF in the perinatal time period.