Appropriate animal models facilitate scientific investigation in the biomedical sciences. The rat is a valuable model for studying physiological processes and is the dominant pre-clinical animal model system used by the pharmaceutical and agro-chemical industries. Estrogens and progestins are key hormones affecting the physiology of the entire organism. These hormones act on their cellular targets through physical interactions with specific ligand-activated transcription factors to regulate gene transcription. Estradiol binds and signals through estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), while progesterone signals through the progesterone receptor (PGR). Research on sex steroid hormones has been central to the development of therapeutics for the treatment of a variety of diseases and health related conditions. Research on the involvement of specific cell signaling pathways have benefitted tremendously from the availability of animal models possessing mutations in critical regulatory genes. This is certainly true for estrogen and progestin signaling pathways. Mice with null mutations at the Esr1, Esr2, and Pgr loci have provided significant insights about the physiology of estrogen and progestin actions. However, the mouse has limitations for some fields of investigation, especially those related to physiology and pharmacology where the rat has proven to be a much better animal model. Considerable advances have been made in genetic manipulation of the rat. These include the application of zinc finger nuclease (ZFN) genome editing to produce rat knock out strains. In this application, we propose to generate and characterize rat models for sex steroid hormone action. We will independently target Esr1, Esr2, and Pgr2. Our characterization of the mutant rat strains will focus on phenotypes associated with the female reproductive tract. Rats possessing disruptions in estrogen and progesterone signaling will provide new tools for biomedical scientists in a range of disciplines, including cancer biology, reproduction, women's health, environmental health, metabolism, immunology, neurosciences, and cardiovascular biology. These new animal models will be made available to the research community.

Public Health Relevance

Sex steroid hormone action underlies the growth and development of the reproductive tract and most other organ systems. Diseases result from disruptions in sex steroid hormone signaling. Development of relevant animal models is a key to understanding diseases associated with dysfunctional sex steroid hormone action and for establishing appropriate and effective diagnostic and therapeutic strategies.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Exploratory/Developmental Grants (R21)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Mirochnitchenko, Oleg
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University of Kansas
Schools of Medicine
Kansas City
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McGreal, Steven R; Rumi, Karim; Soares, Michael J et al. (2017) Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment. Int J Toxicol 36:199-206
Chhibber, Anindit; Woody, Sarah K; Karim Rumi, M A et al. (2017) Estrogen receptor ? deficiency impairs BDNF-5-HT2A signaling in the hippocampus of female brain: A possible mechanism for menopausal depression. Psychoneuroendocrinology 82:107-116
Rumi, M A Karim; Singh, Prabhakar; Roby, Katherine F et al. (2017) Defining the Role of Estrogen Receptor ? in the Regulation of Female Fertility. Endocrinology 158:2330-2343
Kubota, Kaiyu; Cui, Wei; Dhakal, Pramod et al. (2016) Rethinking progesterone regulation of female reproductive cyclicity. Proc Natl Acad Sci U S A 113:4212-7
Rumi, M A Karim; Dhakal, Pramod; Kubota, Kaiyu et al. (2014) Generation of Esr1-knockout rats using zinc finger nuclease-mediated genome editing. Endocrinology 155:1991-9