During the first period of funding. Project 1 focused on addressing the role of progesterone receptors in mediating the cytoprotective effects of progesterone (P4). In particular. Project 1 challenged the dogma that classical progesterone receptors (PR) are the principal mediators of P4's protective effects in the brain by suggesting that recently described membrane-associated progesterone receptors may be equally important. Major findings included the observation that indeed both the classical PR and membrane-associated progesterone receptors, particularly Pgrmcl, cooperate to regulate key cytoprotective mediators, including effectors of the ERK/MAPK pathway (such as ERK1/2 and ERK5) and BDNF. In the continuation of this project, we propose to apply this knowledge to understand whether 1) there is a finite period (i.e., therapeutic window) following steroid hormone deprivation, or with age, where P4's effects on neuroprotection and key mediators of cytoprotection are maintained, and 2) if the relative abundance of PR and Pgrmcl predict sustained protective effects of P4. Further, we will determine whether specific patterns of progesterone receptor expression predict whether P4 complements or antagonizes estrogen's protective effects. Our hypothesis states that the combined expression of the classical PR and the membrane progesterone receptor, Pgrmcl, is required to maintain responsiveness of the brain to P4. Further, we propose that the relative abundance of these two receptors will also predict whether P4 complements estrogen's protective program or whether it antagonizes estrogen's effects. These hypotheses will be tested in cellular models, where the relative levels of PR and Pgrmcl can be manipulated (pharmacologically or using molecular tools), as well as in an animal model of steroid deprivation (ovariectomy), and finally, translated to a human model of ovariectomy (i.e., the surgical menopause). While the loss of estrogen's beneficial effects with increasing post-ovariectomy duration has been described, nothing is known with respect to the response to P4. Thus, the studies proposed herein will reveal a key piece of the """"""""therapeutic window"""""""" puzzle by defining which progesterone receptors are critical determinants of P4's protective effects and importantly, may offer unique insight into how the therapeutic window may be expanded (i.e., through regulation of specific progesterone receptors). Together with the studies proposed in Projects 2 and 3, we expect this program of research to advance our understanding of the neurobiological basis of the """"""""critical window"""""""" of therapeutic opportunity for estrogen and progesterone, a goal that could not be achieved by Project 1 alone.

Public Health Relevance

; We believe this to be the first study to address whether a finite period of brain sensitivity exists for progesterone following steroid deprivation, or as a function of age. Through successful completion of Project 1, we expect to define which progesterone receptors are critical determinants of progesterone's protective effects. Importantly, we expect the data to offer unique insight into how the therapeutic window may be expanded (i.e., through regulation of specific progesterone receptors).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Fort Worth
United States
Zip Code
Nguyen, Trinh; Su, Chang; Singh, Meharvan (2018) Let-7i inhibition enhances progesterone-induced functional recovery in a mouse model of ischemia. Proc Natl Acad Sci U S A 115:E9668-E9677
Izurieta Munoz, Haydee; Gonzales, Eric B; Sumien, Nathalie (2018) Effects of creatine supplementation on nociception in young male and female mice. Pharmacol Rep 70:316-321
Montgomery, Christa L; Johnson, Heather M; Johnston, Thomas P et al. (2018) Mechanisms Underlying Early-Stage Changes in Visual Performance and Retina Function After Experimental Induction of Sustained Dyslipidemia. Neurochem Res 43:1500-1510
Grillo, Stephanie L; Montgomery, Christa L; Johnson, Heather M et al. (2018) Quantification of Changes in Visual Function During Disease Development in a Mouse Model of Pigmentary Glaucoma. J Glaucoma 27:828-841
Mock, J Thomas; Knight, Sherilynn G; Vann, Philip H et al. (2018) Gait Analyses in Mice: Effects of Age and Glutathione Deficiency. Aging Dis 9:634-646
Grillo, Michael A; Grillo, Stephanie L; Gerdes, Bryan C et al. (2018) Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin. Mol Neurobiol :
Kaja, Simon; Payne, Andrew J; Naumchuk, Yuliya et al. (2017) Quantification of Lactate Dehydrogenase for Cell Viability Testing Using Cell Lines and Primary Cultured Astrocytes. Curr Protoc Toxicol 72:2.26.1-2.26.10
Gonzales, Eric B; Sumien, Nathalie (2017) Acidity and Acid-Sensing Ion Channels in the Normal and Alzheimer's Disease Brain. J Alzheimers Dis 57:1137-1144
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2017) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 157:188-211
Engler-Chiurazzi, Elizabeth B; Covey, Douglas F; Simpkins, James W (2017) A novel mechanism of non-feminizing estrogens in neuroprotection. Exp Gerontol 94:99-102

Showing the most recent 10 out of 132 publications