Spermatogenic gene regulation and infertility

生精基因调控与不育

• 批准号: 10615691
• 负责人: Paula Elaine Cohen
• 金额: $ 161.51万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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/10615691
• 关键词: 3' 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; Genome; Genomics; Germ Cells; Goals; Grant; Haploidy; Head; Histones; Human; Infertility; Institution; Life Cycle Stages; Meiosis; Mentorship; Messenger RNA; Methylation; Modification; Morphology; Mus; New York; Nuclear; Participant; Pathogenicity; Patients; Pattern; Pennsylvania; Pilot Projects; Play; Poly A; Polyadenylation; Population; Post-Transcriptional Regulation; Process; Production; Property; Protamines; Proteins; RNA; RNA metabolism; Regulation; Regulator Genes; Regulatory Pathway; Reproduction; Reproductive Biology; Research; Resources; Role; Rural; Schools; Scientist; 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; career; clinically significant; combinatorial; epigenomics; epitranscriptomics; high throughput screening; improved; indexing; innovation; insight; interest; mRNA Stability; mRNA Translation; male; male fertility; meetings; men; mouse model; next generation sequencing; posttranscriptional; 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

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.

康奈尔生殖基因组学中心（CRG）成立于2007年，其目标是利用国家-