Saturday, December 21, 2024
12/21/2024
Abstract: Overall Azoospermia impacts 1% of men globally, which translates to 645,000 men between the ages of 20 and 50 in the United States. It is estimated that genetic causes explain 50% of infertility. Improved knowledge about the genetic basis of infertility and associated overall health comorbidities will aid in the counseling of infertile couples; justify the development of diagnostic screens; and may lead to patient-specific treatment options. In the current personalized medicine era with reduced cost whole genome sequencing and facile genome editing technologies, it is feasible to discover genetic underpinnings of infertility and develop targeted therapies. Project 1 will discover genetic variants in men with unexplained nonobstructive azoospermia (NOA) to identify targets for development of clinical diagnostics or therapy. In addition, Project 1 assemble an international team of experts to develop criteria for review and interpretation of infertility- associated variants to be included in ClinGen, which will facilitate inclusion in clinical diagnostic screens. Project 2 will establish high throughput in vitro gametogenesis platforms and a 100% chimeric mouse strategy for rapid validation of azoospermia-associated variants discovered in Project 1. Project 2 will also evaluate the impact of epigenetic modifiers on primordial germ cell development. Project 3 will provide “gold standard” reproductive phenotyping in mouse models with human NOA associated variants discovered in Project 1 and validated in Project 2. In mouse models of NOA, Project 3 will test the safety and feasibility of Sertoli cell and germ cell gene therapies. Results of all interlinked projects will help justify the use of whole genome sequencing as a diagnostic screen for male infertility and inform the public dialogue on the risks and benefits of gene therapy in and around the germline. Core A will provide administrative oversight and facilitate communications and data exchange among projects and cores to ensure that this P50 program achieves an impact that is greater than the sum of its parts. The Education-Outreach Core will maximize the public impact of this P50 by developing Saturday Academy hands-on laboratory experiences in reproduction and genetics for middle school and high school students in underserved communities in Pittsburgh, Portland and Ithaca. P50 trainees from all sites will also contribute teaching modules to The DataJam, a national nonprofit that runs academic education programs and competitions to engage middle school, high school and community college students in data analytics and critical thinking.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).