权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Pathways Controlling Ovarian Gene Expression

控制卵巢基因表达的分子途径

基本信息

批准号：
8431437
负责人：
CARLOS OSCAR STOCCO
金额：
$ 27.4万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431437
关键词：
Achievement Activins Address Adenoviruses Alleles Androgens Animals Apoptosis Apoptotic Aromatase Biological Assay CYP17A1 gene Cell Culture Techniques Cell Cycle Progression Cell Death Cell Proliferation Cell Survival Cell physiology Cells ChIP-on-chip Code DNA Defect Development Embryo Enzymes Estradiol Estrogens Etiology Female Fertility Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Recombination Genomics Granulosa-Lutein Cells Growth Health Hormones In Vitro Infection Infertility Investigation Knockout Mice Knowledge Light Microarray Analysis Molecular Mus Ovarian Ovarian Cycles Ovarian Diseases Ovarian Granulosa Cell Ovary Paper Pathway interactions Physiological Play Production Publishing Reproduction Reproductive Process Role Staging Steroid biosynthesis Steroids Structure Technology Testing design folliculogenesis gene repression granulosa cell granulosa cell tumor improved functioning in vivo mutant overexpression promoter recombinase response theca cell transcription factor

项目摘要

DESCRIPTION (provided by applicant): Coordinated activation and repression of genes are essential for the normal progress of the ovarian cycle. Ovarian granulosa cells express high levels of the transcription factors GATA-4 and GATA-6. In cell cultures, these transcription factors were shown to play key roles in the expression of enzymes involved in steroidogenesis. We have demonstrated in several recently published papers that GATA-4 is critical for the production of estradiol, which is essential for granulosa cell proliferation and follicle maturation. In addition, the finding that low expression of GATA-4 is associated with follicular cell death suggests that this factor also plays a survival role in the ovary. Because GATA-4 and GATA-6 null mice are embryonic lethal, the ultimate role of GATA in ovarian function remains unknown. This study is therefore designed to determine the physiological role of GATA-4 and GATA-6 in ovarian steroidogenesis, follicular development, and female fertility. The specific aims of this study are: 1- To generate ovarian-specific GATA-4 and GATA-6 null mice in order to find out the explicit roles of these transcription factors in the ovary in vivo. The Cre-lox technology will be used to delete part of the coding region of GATA-4, GATA-6, or their combination. We expect these mice to have severe defects in steroid production and in follicular development. 2- To determine the effect of GATA-4 and GATA-6 deletion on ovarian cells in vitro. Granulosa cells lacking GATA-4, GATA-6, or both will be used to examine the specific roles of these factors in steroidogenesis, cell proliferation, granulosa-cell hormone response, and gene expression. 3- To identify those genes that are regulated by GATA-4 and GATA-6 in fully functional ovaries in vivo, we will use ChIP-on-chip assays. All the results obtained to date indicate that GATA-4 and GATA-6 may play a crucial role in the normal function of the ovary. We expect from this investigation to clearly define the function of GATA-4 and GATA-6 in the steroidogenic capacity and growth of granulosa cells, to determine whether GATA-4 and GATA-6 have redundant effects on these cells, and to identify GATA-4 and GATA-6 target genes in the ovary. This study will not only provide critically important information on the regulatory mechanism underlying normal ovarian function but also may shed light on ovarian diseases due to improper granulosa cell function such as granulosa cell tumors and infertility.

描述（由申请人提供）：基因的协调激活和抑制对于卵巢周期的正常进展至关重要。卵巢颗粒细胞表达高水平的转录因子加塔-4和加塔-6。在细胞培养中，这些转录因子被证明在参与类固醇生成的酶的表达中发挥关键作用。我们在最近发表的几篇论文中证明，加塔-4对雌二醇的产生至关重要，而雌二醇对颗粒细胞增殖和卵泡成熟至关重要。此外，加塔-4的低表达与卵泡细胞死亡相关的发现表明，该因子在卵巢中也起着存活作用。由于加塔-4和加塔-6缺失小鼠是胚胎致死的，因此加塔在卵巢功能中的最终作用仍然未知。因此，本研究旨在确定加塔-4和加塔-6在卵巢类固醇生成、卵泡发育和女性生育力中的生理作用。本研究的具体目的是：1-建立卵巢特异性加塔-4和加塔-6基因敲除小鼠，以明确这些转录因子在体内卵巢中的作用。Cre-lox技术将用于删除加塔-4、加塔-6或其组合的部分编码区。我们预计这些小鼠在类固醇产生和卵泡发育方面有严重缺陷。2-研究加塔-4和加塔-6缺失对体外培养的卵巢上皮细胞的影响。缺乏加塔-4、加塔-6或两者都缺乏的颗粒细胞将被用于检查这些因子在类固醇生成、细胞增殖、颗粒细胞激素应答和基因表达中的特定作用。3-为了在体内鉴定在完全功能的卵巢中由加塔-4和加塔-6调节的那些基因，我们将使用ChIP芯片测定。迄今为止获得的所有结果表明，加塔-4和加塔-6可能在卵巢的正常功能中起关键作用。我们期望从这项研究中清楚地定义加塔-4和加塔-6在颗粒细胞的类固醇生成能力和生长中的功能，以确定加塔-4和加塔-6是否对这些细胞具有冗余效应，并确定卵巢中的加塔-4和加塔-6靶基因。这项研究不仅将提供至关重要的信息，正常卵巢功能的调节机制，但也可能揭示卵巢疾病，由于不适当的颗粒细胞功能，如颗粒细胞瘤和不孕症。