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What is the context of this research?

The fundamental question I am trying to answer is whether PARP inhibitors can be used to prevent the production of BRCA mutant gametes. This may provide a mechanism to prevent transmission of BRCA mutations to offspring.



To test the hypothesis that BRCA mutation transmission can be prevented with PARP inhibitors, an animal model that is highly relevant to human BRCA mutation carriers will be used. Brca mutant mice develop breast tumors that histologically resemble human BRCA mutant cancers and Brca deficient cells from these mice are exquisitely sensitive to PARP inhibition, similarly to humans. The Mendelian ratio of inheritance of Brca mutations is identical to that of human BRCA carriers. Therefore heterozygous mutant mice can be used to determine whether PARP inhibitor administration during conception can prevent transmission of BRCA mutations to offspring.

What is the significance of this project?

This project matters to me because I strongly believe that it could really help BRCA mutation carriers. Currently carriers of BRCA mutations are faced with a difficult choice when they are planning to have children. They can take the risk that their children will inherit the BRCA mutation from them (a 50% chance), resulting in an 80% chance that they will develop breast or ovarian cancer if they are female. The only other options are adoption, selective termination, or pre-implantation genetic diagnosis /IVF. All of which have significant drawbacks. If this project is successful, PARP inhibitors could be used by male BRCA mutation carriers during conception to selectively deplete BRCA mutant sperm, and thereby prevent the transmission of BRCA mutations to offspring. This would provide a cost effective and non-invasive way to prevent transmission of BRCA mutations to offspring.



Importantly this study will provide proof of principle that drugs can be used to prevent transmission of mutations to offspring. This approach could then be broadly applied to prevent genetically inherited diseases.

What are the goals of the project?

The total cost for this experiment is $15,000. The animal experiments will be conducted by Dale Cowley, Ph.D. from the University of North Carolina Animal Models Core via Science Exchange.



Male Brca1+/- heterozygous mutant mice will be treated with olaparib (a PARP inhibitor) or vehicle control and bred with wild type female mice. The resultant pups will be genotyped to determine whether PARP inhibitor treatment prevents the transmission of Brca1 mutations, resulting in fewer Brca1 mutant carrier pups being born (50% of pups are expected to carry the mutation).



Details of the experimental design are available in the lab notes tab.