This application for an administrative supplement to NIH Grant U42 OD012210, the parent grant of the Mutant Mouse Resource and Research Center (MMRRC) at UC Davis, is submitted in response to NOT-OD-20-049 Notice of Special Interest: Administrative Supplements for Research on Sex/Gender Influences. This supplement will address the first of five objectives of the 2019-2023 Trans-NIH Strategic Plan for Women?s Health Research ?Advancing Science for the Health of Women?: Advancing rigorous research that is relevant to the health of women. This application proposes pre-clinical research using mouse models of patient-specific genomic variants as one of three sex-based study types, and includes two of the three proscribed sex-based research approaches: addition of the opposite sex (in this case, female) and increasing sample size. To do so, we will conduct the following 3 specific aims: 1) generate cohorts of female mice for variants nominated from male patients; 2) conduct in vivo targeted phenotyping of female cohorts of mice; and 3) promote awareness and availability of genetic variants in female mouse models. We propose to study the pathophysiological consequences of genetic variation in female mice for up to 10 genomic variants we have already studied in male mice. The purpose of the proposed preclinical research project is to increase mechanistic understanding of sex differences in phenotypic expression of genetic variants using comparative studies of male and female physiological systems in mice.
This proposal from the Mutant Mouse Resource and Research Center at UC Davis (MMRRC-UC Davis) intends to address areas of need in preclinical research that are outlined in the 2019-2023 Trans-NIH Strategic Plan for Women?s Health Research ?Advancing Science for the Health of Women?. Specifically, by studying the pathophysiological consequences of human genetic variation in female mice, we will increase mechanistic understanding of sex differences in phenotypic expression of genetic variants in humans. Further, because adhering to high standards of scientific rigor is critical for generating reproducible results, the research we propose has been rigorously designed, including consideration of the influences of sex, and will contribute to the NIH agenda to promote research that seeks to improve the health of women.
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