Grant Number:	7R01CA290670-02 Interpret this number
Primary Investigator:	Lamb, Dolores
Organization:	Children'S Mercy Hosp (Kansas City, Mo)
Project Title:	DNA Repair Deficiencies in Infertile Men and Cancer Risk
Fiscal Year:	2024

There is a need to identify the causes of the most severe form of male infertility, non-obstructive azoospermia (NOA), where there is spermatogenic failure resulting in an ejaculate with no sperm. Yet, there is a poor understanding of the mechanisms regulating sperm production and the genetic, genomic or epigenetic defects that underlie NOA beyond structural and numerical chromosomal defects, a few endocrinopathies and gene defects. NOA men have an increased risk of serious diseases, such as cancer, when compared with fertile men or men with sperm in their ejaculates. However, the link between their infertility and their increased disease risk has remained elusive. This project will build on the intriguing data obtained to date showing the presence of deficiencies of mismatch repair (MMR) and/or MSH5 expression from gene mutation or epigenetic variant is present in NOA men resulting in an abnormal cellular response to alkylating agent DNA damage, genomic instability and a deficiency of double-strand break repair suggesting the presence of DNA repair defects. MMR or MSH5 deficiency can cause these cellular responses and is associated with malignancies (testis, hematologic, colon, prostate, breast, thyroid) and infertility due to ovarian and spermatogenic failure. We will test the hypothesis that the decreased mismatch repair and/or MSH5 expression in a subset of infertile men leads not only to decreased genetic stability, impaired DNA break, and defective homologous recombination but also leads malignancies and NOA. We hypothesize that mismatch repair and/or MSH5 deficiency is a common link between infertility and the increased risk of malignancies. These studies will provide insights into an unrecognized etiology of NOA and the non-reproductive related health risks, specifically cancers associated with NOA.





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