The Role of Retinoic Acid-regulated microRNAs in Spermatogonial Differentiation

视黄酸调节的 microRNA 在精原细胞分化中的作用

• 批准号: 8114661
• 负责人: MICHAEL D GRISWOLD
• 金额: $ 22.04万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114661
• 关键词: Biology; Contraceptive methods; Data; Development; Diagnostic; Etiology; Functional RNA; Gene Expression; Gene Expression Profile; Genes; Goals; Human; Infertility; Link; Male Contraceptions; Male Contraceptive Agents; Male Infertility; Mediating; MicroRNAs; Modeling; Molecular; Morale; Mus; Outcome Study; Play; Prevention approach; Proteins; Proteomics; RNA; RNA Sequences; Regulation; Regulator Genes; Reproduction; Research; Retinoids; Role; Signal Transduction; Spermatogenesis; Spermatogonia; Testing; Tretinoin; Undifferentiated; Vitamin A; base; gene function; innovation; insight; male; men; therapeutic target

DESCRIPTION (provided by applicant): Retinoic acid (RA) signaling is central to the spermatogonial differentiation. Despite this fact, the molecular mechanisms that govern the spermatogonial differentiation remain poorly understood. While several groups are studying RA-mediated cellular transcriptome changes during spermatogonial differentiation, the effect of RA on gene expression at the posttranscriptional level is yet to be elucidated. MicroRNAs (miRNAs) are a new class of short non-coding RNA genes that function as sequence-specific posttranscriptional regulators of gene expression. It has become apparent that miRNAs play important roles during spermatogenesis. However, it is unclear whether miRNAs can be regulated by RA signaling and could thereby contribute to spermatogonial differentiation. Our long-term goal is to identify the essential networks involved in spermatogonial differentiation. Our central hypothesis is that RA regulates miRNAs expression and these miRNAs in turn modulate expression of key genes encoding protein responsible for spermatogonial differentiation. In this R21 application, we propose to determine how RA-regulated miRNAs potentially contribute to spermatogonial differentiation. Specifically, in Aim 1 we hypothesize that expression of a subset of miRNAs is regulated by RA signaling and we propose to identify the RA-regulated miRNAs during spermatogonial differentiation. In Aim 2 we hypothesize that RA-regulated miRNAs modulate expression of key downstream proteins to enhance the effect of RA on spermatogonia differentiation and we propose to establish the potential functional roles of selected RA-regulated miRNAs in spermatogonial differentiation. Completion of the proposed research will help identify regulatory networks that control spermatogonial differentiation. A better understanding of spermatogonial differentiation has important implications for male reproduction and contraception. PUBLIC HEALTH RELEVANCE: Male factor infertility occurs in about 10% of men, although the etiology of impaired spermatogenesis is rarely identified. Retinoic acid (RA) is critical for spermatogonial differentiation, an initial step of spermatogenesis. The purpose of this proposal is to explore the role of RA-targeted microRNAs in the regulation of spermatogonial differentiation, which has important implications for retinoid biology and male reproduction.

描述（由申请人提供）：视黄酸（RA）信号传导对于精原细胞分化至关重要。尽管如此，人们对控制精原细胞分化的分子机制仍然知之甚少。虽然几个小组正在研究精原细胞分化过程中 RA 介导的细胞转录组变化，但 RA 对转录后水平基因表达的影响尚未阐明。 MicroRNA (miRNA) 是一类新型的短非编码 RNA 基因，可作为基因表达的序列特异性转录后调节因子。很明显，miRNA 在精子发生过程中发挥着重要作用。然而，目前尚不清楚 miRNA 是否可以通过 RA 信号传导进行调节，从而有助于精原细胞的分化。我们的长期目标是确定参与精原细胞分化的重要网络。我们的中心假设是 RA 调节 miRNA 的表达，而这些 miRNA 反过来又调节编码负责精原细胞分化的蛋白质的关键基因的表达。在此 R21 应用中，我们建议确定 RA 调节的 miRNA 如何潜在地促进精原细胞分化。具体而言，在目标 1 中，我们假设 miRNA 子集的表达受 RA 信号传导调节，并且我们建议鉴定精原细胞分化过程中 RA 调节的 miRNA。在目标 2 中，我们假设 RA 调节的 miRNA 调节关键下游蛋白的表达，以增强 RA 对精原细胞分化的影响，并且我们建议确定选定的 RA 调节的 miRNA 在精原细胞分化中的潜在功能作用。完成拟议的研究将有助于确定控制精原细胞分化的调控网络。更好地了解精原细胞分化对于男性生殖和避孕具有重要意义。 公共卫生相关性：尽管精子发生受损的病因很少被确定，但大约 10% 的男性患有男性因素不育。视黄酸（RA）对于精原细胞分化至关重要，精原细胞分化是精子发生的第一步。本提案的目的是探索 RA 靶向的 microRNA 在精原细胞分化调节中的作用，这对类维生素A生物学和男性生殖具有重要意义。