P50HD104454

Spermatogenic Gene Regulation and Infertility

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 epitrancriptomic 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. Additionally, 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 epitrancriptomic 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 epitrancriptomic 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.

Cornell University

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Ithaca, New York 148537202 United States

Single Zip Code

National Centers for Translational Research in Reproduction and Infertility (NCTRI) (P50 Clinical Trial Optional) (RFA-HD-21-012)

Amendment Since initial award the total obligations have increased 392% from $1,647,764 to $8,106,807.