Investigating the relationship between genome mutagenesis, fertility, and health in fertile and infertile men
Ended Project Grant Awarded Last action
- Award ID
- F31HD115390
- Recipient
-
University Of Utah UEI LL8GLEVH6MG3
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $276,150
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date
- Place of performance
- Salt Lake City, UT 84112, USA
Award details come from USAspending.gov.
Description
- Abstract
- Male infertility is a highly prevalent condition, impacting ~7% of men. However, clinical management is complex, as roughly half of male infertility cases are idiopathic. Furthermore, a diagnosis of male infertility has health ramifications even beyond an affected individual's reproductive health. Epidemiologic studies associate infertile men and their families with poor somatic health, including increased risks for testicular cancer, prostate cancer, cardiovascular disease, congenital abnormalities, and reduced lifespans. To explain these associations, my CO-sponsor, DR. Aston, found significant overlap in DNA repair genes involved in male infertility and human cancers. Additionally, our lab found that fertile men in the top quartile of age-adjusted germline mutation rates died five years earlier than men in the lowest quartile. When translating these findings to infertile men, mutation accumulation in the germline may be connected to deleterious somatic mutagenesis in the same infertile male, potentially resulting in reduced fertility and poor somatic health, respectively. Currently, the exact mechanisms underlying impaired spermatogenesis in infertile men are poorly understood. For example, while DNA fragmentation and aneuploidy rates have extensively been studied in the sperm of fertile and infertile men, the relationship between male infertility and germline DE novo mutagenesis, or the accumulation of spontaneous single nucleotide alterations in a male's spermatogonial stem cell (SSC) lineage, has been ignored. Additionally, IT is unknown whether reduced sperm production in infertile men is related to an abnormal SSC composition or distribution of SSC states. Given these knowledge gaps, there exists a critical need to comprehensively characterize the mutational landscape directly in the sperm of fertile and infertile men, as such analyses may illuminate key biological and mutagenic processes involved in male infertility. This project will use duplex sequencing to explore connections between genome hypermutation, male infertility, and poor health. Specifically, I will investigate whether infertile, oligozoospermic men harbor elevated degrees of germline and somatic mutagenesis relative to fertile, normozoospermic men. Aim 1 will examine germline mutation rates from the bulk sperm of normozoospermic men, including samples collected from the same individual spanning multiple decades. Aim 2 will determine if infertile men exhibit increased rates of germline mutagenesis compared to age-matched normozoospermic men. Finally, aim 3 will test whether oligozoospermic men harbor elevated somatic mutation rates compared to fertile controls. Completing these aims will establish germline and somatic mutagenesis as hallmark genetic features of male infertility. Furthermore, novel insights gained from this analysis will inform future investigations into upstream biological and cellular processes contributing to genome hypermutation, impaired spermatogenesis, and associated somatic comorbidities.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$20,613 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $141 | |
| Amendment | $141 | |
| Amendment | $141 | |
| Amendment | $25,431 | |
| Amendment | $25,431 | |
| Amendment | $25,431 | |
| Amendment | $25,431 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Original award | $47,694 |
Show all 20
Quick answers
Who received award F31HD115390?
F31HD115390 was awarded to University Of Utah by National Institute of Child Health and Human Development (National Institutes of Health) on September 30, 2024.
How much is award F31HD115390 worth?
$276,150 has been obligated on F31HD115390.
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