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）：促性腺激素合成并分泌异质二聚体糖蛋白黄体激素（LH）和卵泡刺激激素（FSH）至关重要生殖功能。编码共同α亚基（CGA）和激素特异性β亚基（LHB和FSHB）的基因通过下丘脑促性腺激素释放激素，类固醇和性腺肽，抑制素和激活素协调调节。尽管大量知识已经积累了促性腺激素β亚基的转录控制，但这些基因的转录后机制尚不清楚。最近，由RNA核酸内切酶III DICER产生的微RNA（miRNA）已成为基因表达，mRNA稳定性和蛋白质合成的关键调节剂。缺乏调节促性腺肿瘤并因此生殖功能的miRNA的知识。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，迪切尔是促性腺激素中miRNA生物发生的关键因素，并且在促性腺激素合成中起着至关重要的作用，因此在生殖功能中起着至关重要的作用。在特定目标1中，我们将通过Cre-Lox技术有条件地在促性腺激素中删除DICER，并分析促性腺激素的合成和分泌。此外，我们将使用新型的小鼠菌株，其中促性腺激素在正常或激活素受体-II（ACVR2）NULL遗传背景上用GFP标记为GFP。通过基于GFP荧光和由ACVR2调节的miRNA，将从这些小鼠分类中分离出促性腺激素的纯种群。在特定的目标2中，将确定促性腺激素缺失因促性腺激素缺失而导致的生殖表型。这些研究应提供有关DICER-促性腺激素依赖的miRNA的新知识，并确定促性腺激素分泌的新型文字后机制。促性腺激素分泌机制的描述是繁殖生理学的基础，并为诊断和治疗促性腺激素依赖性的生育/不育疾病提供了长期临床益处。公共卫生相关性：我们的研究应提供有关如何产生称为Micro RNA的小型RNA的新知识，可以调节卵泡激素（FSH）的合成和分泌，并从垂体中产生刺激性的激素（FSH）和黄体生成激素（LH）。 FSH和LH分泌机制的描述是繁殖生理学的基础，并为诊断和治疗FSH依赖性生育/不育疾病提供了临床益处。其中一些包括过度刺激综合征，闭经和睾丸缺陷。