Basic and clinical research is revealing that various noncoding and small RNAs play important and diverse roles in germ cell development and quality, including X/Y silencing during meiosis, gene regulation, DNA damage responses, and protection of the genome against transposable elements. Indeed, mammalian germ cells are known to hart)or multiple small RNA species, including small interfering RNAs (siRNA), microRNAs (miRNA), and germline-specific PlWI-interacting RNAs (piRNA). However, their mechanistic roles in gametogenesis and human infertility are largely uncharacterized. The Cornell Center for Reproductive Genomics (CRG), established in 2006, has developed emerging strengths in the area of small RNA biology to address these gaps in our understanding. The goal of these studies is to elucidate the role of small RNA pathways in the events that give rise to viable euploid gametes. Four projects are proposed: Project I (PI: Andrew Crimson) will define the temporal profile of small RNA expression and small RNA targets throughout spermatogenesis, focusing on the onset of, and progression through, prophase I in the mouse; Project II (PI: Darius Paduch) will explore the roles and expression of microRNAs in human male germ cell and somatic compartments, and will examine changes in the profiles of testicular small RNAs In infertile men; Project III (PI: Paula Cohen) will explore the role of the Argonaute family of small RNA binding proteins in the critical process of meiotic silencing during prophase I in mice; and Project IV (PI: John Schimenti) will examine how the process of DNA replication licensing in mammalian germ cells is controlled by post-transcriptional control mediated by microRNA, miR34. Three cores are proposed: an Administrative core, and Outreach Core and an RNA sequencing core, the latter being open to all SCCPIR members. Collectively, these studies represent the most comprehensive analysis of small RNA pathways in mammalian gametogenesis to date, and will provide a cutting-edge program in small RNA regulatory processes that will be a unique and timely addition to the SCCPIR network. The combined focus on comparative analysis of small RNA pathways in the germline is likely to contribute greatly to the understanding of how these pathways may function to ensure the production of healthy gametes.

Public Health Relevance

The formation of mature gametes (eggs and sperm) is of central importance for reproduction and fertility and a large percentage of infertility cases can be attributed directly to defective gametes, with > 20% of human conceptions being lost as a result of errors in meiosis. This center grant proposal seeks to address the role of small RNA pathways in gametogenesis and, more importantly, what role small RNAs might play in the dysfunction that gives rise to defective gametes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD076210-04
Application #
9250640
Study Section
Special Emphasis Panel (ZHD1-DSR-L (54))
Program Officer
Moss, Stuart B
Project Start
2014-04-14
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$1,313,972
Indirect Cost
$479,406
Name
Cornell University
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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