Spermatogenic gene regulation and infertility

生精基因调控与不育

基本信息

批准号：
10157198
负责人：
Paula Elaine Cohen
金额：
$ 164.78万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10157198
关键词：
3&apos Untranslated Regions ATAC-seq Address Affect Alternative Splicing Aneuploidy Assisted Reproductive Technology Benchmarking Biology Bromodomain Cells Child Chromatin Chromatin Remodeling Factor Clinical Collaborations Communities Complex Couples Defect Deposition Development Ensure Environment Epigenetic Process Event Faculty Fertility Fertilization Foundations Gene Expression Gene Expression Profile Gene Expression Regulation Generations Genes Genetic Genetic Transcription Genomics Germ Cells Goals Grant Haploidy Head Histones Human Infertility Institutional support resources Life Cycle Stages Meiosis Mentorship Messenger RNA Methylation Modification Morphology Mus New York Nuclear Participant Pathogenicity Patients Pattern Pennsylvania Pilot Projects Play Polyadenylation Population Post-Transcriptional Regulation Process Production Property Protamines Proteins RNA RNA metabolism Regulation Regulator Genes Regulatory Pathway Reproduction Reproductive Biology Research Role Rural Schools Scientist Seeds Site Source Specialized Center Sperm Count Procedure Sperm Motility Spermatocytes Spermatogenesis Spermatogenic Cell Spermiogenesis Technology Testing Testis Time Transcriptional Regulation Translations United States Universities Untranslated RNA Variant base career clinically significant combinatorial epigenomics epitranscriptomics high throughput screening improved indexing innovation insight interest mRNA Stability male male fertility meetings men mouse model next generation sequencing recruit reproductive role model school district sperm cell sperm function sperm morphology sperm quality stem cells symposium transcriptome transcriptome sequencing transcriptomics translational approach underserved community

项目摘要

The Cornell Center for Reproductive Genomics (CRG) was founded in 2007 with the goal of leveraging state-of- the-art genomics technologies for understanding the biology of the mammalian germ cell. More specifically, our goal has been to understand the genetic, epigenetic, and epitranscriptomic basis for the generation of viable healthy gametes and to explore how alterations in these events could contribute to human infertility. It is well known that disruption of genes required for regulating all aspects of gene expression, including chromatin modifiers, the transcription machinery, and components of post-transcriptional regulatory pathways, leads to the formation of spermatozoa with abnormal head morphology in the mouse, while sperm from men with increased abnormal sperm morphology significantly higher rates of chromosomal aneuploidy, chromatin compaction defects, and altered transcriptome profiles compared to sperm from fertile men. Thus, in this application, we seek to understand how transcriptional, post-transcriptional, and epitranscriptomic regulation of gene expression and chromatin state contributes to the differentiation of haploid germ cells into mature spermatozoa. Three projects are proposed and three cores are proposed. PROJECT I (Danko and Cohen) will focus on the importance of transcriptional regulation of gene expression at the exit from meiosis and entry into spermiogenesis, with a focus on the role of the bromodomain protein, BRDT in facilitating transcriptional shutdown and thus permitting appropriate histone-to-protamine replacement and nuclear compaction. PROJECT II (Grimson, Schimenti, Hwang) will focus on mechanisms and functions of post-transcriptional processing and regulation of mRNAs during spermiogenesis and whether defects in these processes can underlie defects in sperm morphology in patients seeking assisted reproductive technologies. PROJECT III (Jaffrey) will explore the dynamics of N6-methyladenosine (M6A) and N6, 2’-O-dimethyladenosine (m6Am) modifications on RNA through spermatogenesis in mice and in men, and the importance of these epitranscriptomic changes for the production of healthy sperm in mice and men. These studies will be supported by a well-established ADMINISTRATIVE CORE (Cohen) that will facilitate close interactions through regular meetings, trainee events, pilot and seed grants, and our popular “Tri-Repro” Annual Symposium. Our state-of- the-art GENOME INNOVATION CORE (Grenier) will serve as an Innovation Hub for exploring all aspects of gene regulation in reproduction, specializing in a range of next generation sequencing technologies to support the projects. Finally, our OUTREACH CORE (Lin) will provide lab opportunities for nearby, and traditionally underserved, school districts throughout upstate New York, at the same time sending our trainees and faculty out to these communities as role models for young budding scientists. Our center will benefit from the strong research and clinical integration we have established over the past 13 years, by robust and unequivocal institutional support, and by the outstanding scientific environment provided by Cornell University.

康奈尔（Cornell）生殖基因组学中心（CRG）成立于2007年，目的是利用最新 ART基因组学技术用于理解哺乳动物生殖细胞的生物学。更具体地说，我们的目标是了解生成可行的遗传，表观遗传学和表演基础健康的游戏节目并探索这些事件中的变化如何有助于人类不育。很好知道确定基因表达的所有方面所需的基因的破坏，包括染色质转录后调节途径的修饰符，转录机械和组件，导致在小鼠中形成具有异常头形态的精子，而男性的精子增加异常的精子形态明显更高的染色体非整倍性，染色质压实率与肥沃男性的精子相比，缺陷和转录组轮廓改变。在此应用程序中，我们寻求了解基因表达的转录，转录后和表演的调节染色质状态有助于将单倍体生殖细胞分化为成熟的精子。三提出了项目，并提出了三个核心。项目I（Danko和Cohen）将专注于从减数分裂出口出口并进入的基因表达的转录调节的重要性精子发生，重点是溴结构域蛋白的作用，BRDT在支持转录方面关闭，从而允许适当的组蛋白到脑胺替代和核压实。项目II（Grimson，Schimenti，Hwang）将重点关注转录后的机制和功能精子发生过程中mRNA的处理和调节以及这些过程中的缺陷是否可以寻求辅助生殖技术的患者的精子形态缺陷的基础。项目三（Jaffrey）将探索N6-甲基读二氨酸（M6A）和N6、2'-O-二甲基二苯胺（M6AM）的动力学通过小鼠和男性的精子发生对RNA的修改，这些的重要性小鼠和男性健康精子的生产的表面转录变化。这些研究将得到支持由完善的行政核心（Cohen），该核心将有助于通过常规会议，学员活动，飞行员和种子赠款以及我们流行的“ Tri-Repro”年度研讨会。我们的最新 The-Art Genome Innovation Core（Grenier）将作为探索各个方面的创新枢纽繁殖中的基因调节，专门研究一系列下一代测序技术以支持项目。最后，我们的外展核心（林）将为附近以及传统上提供实验室机会服务不足的，整个纽约州北部的学区，同时发送我们的培训和教职员工向这些社区作为年轻萌芽科学家的榜样。我们的中心将受益于强者我们在过去13年中建立的研究和临床整合，通过强大而明确的机构支持，以及康奈尔大学提供的杰出科学环境。