Spermatogenic gene regulation and infertility

生精基因调控与不育

基本信息

批准号：
10398873
负责人：
Paula Elaine Cohen
金额：
$ 161.56万
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/10398873
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.

康奈尔大学生殖基因组学中心 (CRG) 成立于 2007 年，旨在利用现有技术用于了解哺乳动物生殖细胞生物学的最先进的基因组学技术。目标是了解产生可行的遗传、表观遗传和表观转录组学基础健康的配子并探索这些事件的改变如何导致人类不育，这很好。已知破坏基因需要调节基因表达的各个方面，包括染色质修饰子、转录机制和转录后调控途径的组成部分，导致小鼠精子形成头部形态异常，而男性精子形成增加精子形态异常染色体非整倍体、染色质压缩率显着升高与可育男性的精子相比，缺陷和转录组谱发生了改变。因此，在本申请中，我们试图了解基因表达的转录、转录后和表观转录组调控染色质状态有助于单倍体生殖细胞分化为成熟精子。拟议的项目和三个核心项目 I（Danko 和 Cohen）将重点关注减数分裂退出和进入减数分裂时基因表达转录调控的重要性精子发生，重点关注溴结构域蛋白 BRDT 在促进转录中的作用关闭，从而允许适当的组蛋白到鱼精蛋白的替换和核压缩。项目 II（Grimson、Schimenti、Hwang）将重点研究转录后的机制和功能精子发生过程中 mRNA 的加工和调节是否以及这些过程中的缺陷可以寻求辅助生殖技术的患者精子形态缺陷的根源。 (Jaffrey) 将探索 N6-甲基腺苷 (M6A) 和 N6, 2'-O-二甲基腺苷 (m6Am) 的动力学小鼠和男性精子发生过程中 RNA 的修饰，以及这些修饰的重要性小鼠和男性健康精子产生的表观转录组变化将得到支持。由完善的行政核心（科恩）负责，该核心将通过定期促进密切互动会议、实习生活动、试点和种子资助，以及我们广受欢迎的“Tri-Repro”年度研讨会。最先进的基因组创新核心（Grenier）将作为创新中心，探索基因组创新的各个方面生殖中的基因调控，专门研究一系列下一代测序技术以支持最后，我们的 OUTREACH CORE（林）将为附近的传统项目提供实验室机会。纽约州北部服务不足的学区，同时派遣我们的学员和教职人员我们的中心将受益于这些社区作为年轻科学家的榜样。我们在过去 13 年中通过稳健而明确的方式建立了研究和临床一体化机构的支持，以及康奈尔大学提供的出色的科学环境。