Role of Dicer in Gonadotrope and Reproductive Function

Dicer 在促性腺激素和生殖功能中的作用

基本信息

批准号：
8301917
负责人：
T. RAJENDRA KUMAR
金额：
$ 7.55万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301917
关键词：
3&apos Untranslated Regions Activin Receptor Activins Affect Amenorrhea Anterior Pituitary Gland Applications Grants Binding Biogenesis Cattle Cell Line Cell Separation Clinical Computer Simulation Defect Development Diagnosis Disease Double-Stranded RNA Embryo Endoribonucleases Event Family Fertility Fluorescence Follicle Stimulating Hormone Gametogenesis Gene Expression Gene Expression Regulation Genes Genetic Genetic Models Genetic Transcription Glycoproteins Goals Gonadal Steroid Hormones Gonadotrope Cell Gonadotropin Hormone Releasing Hormone Gonadotropins Growth Home environment Hormones Hypothalamic structure In Vitro Infertility Knowledge Label Lead Lesion Luteinizing Hormone Mediating Messenger RNA MicroRNAs Molecular Mouse Strains Mus Ovarian Hyperstimulation Syndrome Peptides Phenotype Physiology Pituitary Gland Play Population Positioning Attribute Post-Transcriptional Regulation Protein Biosynthesis Proteins Regulation Regulator Genes Reproduction Research Role Secondary to Small Interfering RNA Small RNA Steroid biosynthesis Syndrome Technology Testing Tissues Transcription Factor 3 Transcriptional Regulation Transgenes Untranslated Regions Work base cell type combinatorial endonuclease III endoribonuclease human DICER1 protein improved in vitro Model in vivo inhibin mRNA Stability mouse model novel novel therapeutics promoter reproductive reproductive function

项目摘要

DESCRIPTION (provided by applicant): Gonadotropes synthesize and secrete heterodimeric glycoproteins luteinizing hormone (LH) and follicle stimulating hormone (FSH) that are critical for reproductive function. The genes encoding the common alpha subunit (Cga) and the hormone-specific beta subunits (Lhb and Fshb) are coordinately regulated by hypothalamic gonadotropin-releasing hormone, steroids and gonadal peptides, inhibin and activin. Although a wealth of knowledge has accumulated on transcriptional control of gonadotropin beta subunits, post- transcriptional mechanisms of these genes are unknown. Recently, micro RNAs (miRNAs) produced by Dicer, an RNA endonuclease III, have emerged as key regulators of gene expression, mRNA stability and protein synthesis. Knowledge on miRNAs that regulate gonadotrope and consequently reproductive function is lacking. Our long-term research goal is to elucidate the in vivo mechanisms that regulate gonadotropin synthesis and secretion. The central hypothesis is that Dicer is a key factor in miRNA biogenesis in gonadotropes and plays essential roles in gonadotropin synthesis and consequently reproductive function. In Specific Aim 1, we will conditionally delete Dicer exclusively in gonadotropes by cre-lox technology and analyze gonadotropin synthesis and secretion. Additionally, we will use novel mouse strains, in which gonadotropes are labeled with GFP on a normal or activin receptor-II (Acvr2) null genetic background. Pure populations of gonadotropes will be isolated from these mice by cell sorting based on GFP fluorescence and miRNAs regulated by Acvr2 identified. In Specific Aim 2, reproductive phenotypes secondary to changes in gonadotropins as a result of Dicer deletion in gonadotropes will be determined. These studies should provide new knowledge on Dicer - dependent miRNAs in gonadotropes and identify novel post-transcriptional mechanisms for gonadotropin secretion. Delineation of mechanisms of gonadotropin secretion is fundamental to physiology of reproduction and offers long-term clinical benefits of diagnosing and treating gonadotropin-dependent fertility/infertility disorders. PUBLIC HEALTH RELEVANCE: Our studies should provide new knowledge on how Dicer that produces small RNAs called micro RNAs regulates synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from pituitary gland. Delineation of mechanisms of FSH and LH secretion is fundamental to physiology of reproduction and offers clinical benefits of diagnosing and treating FSH-dependent fertility/infertility disorders. Some of these include hyperstimulation syndromes, amenorrhea and testicular defects.

描述（由申请人提供）：促性腺激素合成和分泌异二聚体糖蛋白黄体生成素（LH）和卵泡刺激素（FSH），这对于生殖功能。编码共同α亚基（Cga）和激素特异性β亚基（Lhb和Fshb）的基因受到下丘脑促性腺激素释放激素、类固醇和性腺肽、抑制素和激活素的协调调节。尽管在促性腺激素β亚基的转录控制方面积累了丰富的知识，但这些基因的转录后机制尚不清楚。最近，由 Dicer（一种 RNA 核酸内切酶 III）产生的微小 RNA (miRNA) 已成为基因表达、mRNA 稳定性和蛋白质合成的关键调节因子。关于调节促性腺激素和生殖功能的 miRNA 的知识尚缺乏。我们的长期研究目标是阐明调节促性腺激素合成和分泌的体内机制。中心假设是 Dicer 是促性腺激素中 miRNA 生物发生的关键因素，在促性腺激素合成和生殖功能中发挥重要作用。在具体目标1中，我们将通过cre-lox技术有条件地删除促性腺激素中专门的Dicer，并分析促性腺激素的合成和分泌。此外，我们将使用新的小鼠品系，其中促性腺激素在正常或激活素受体 II (Acvr2) 无效遗传背景上用 GFP 标记。根据 GFP 荧光和鉴定出的 Acvr2 调节的 miRNA，通过细胞分选从这些小鼠中分离出纯促性腺激素群体。在具体目标 2 中，将确定由于促性腺激素中 Dicer 缺失导致促性腺激素变化继发的生殖表型。这些研究应该提供关于促性腺激素中 Dicer 依赖性 miRNA 的新知识，并确定促性腺激素分泌的新转录后机制。促性腺激素分泌机制的描述是生殖生理学的基础，并为诊断和治疗促性腺激素依赖性生育/不育疾病提供长期临床益处。公共健康相关性：我们的研究应该提供关于 Dicer 产生小 RNA（称为 micro RNA）如何调节垂体促卵泡激素 (FSH) 和黄体生成素 (LH) 的合成和分泌的新知识。 FSH 和 LH 分泌机制的描述是生殖生理学的基础，并为诊断和治疗 FSH 依赖性生育/不育疾病提供临床益处。其中一些包括过度刺激综合征、闭经和睾丸缺陷。