Uterine leiomyomas occur in approximately 77% of all women in the United States and can cause severe morbidity and infertility. To date, there is no effective treatment for leiomyomas besides hysterectomies. In this application, we hope to better understand the biology behind uterine leiomyoma growth at the cellular and molecular level. Specifically, there is evidence that the hormone progesterone causes leiomyomas to grow and once we understand how progesterone, through its receptor, PR, promotes leiomyoma growth, we can begin to study ways to inhibit this process. We have gathered evidence that progesterone can activate the AKT pathway which is a pathway that is involved in cell proliferation and survival. In addition, we have found that progesterone, through PR, can attenuate the action of a transcription factor, FOXOI, which is a member ofthe AKT pathway as well as a molecule that inhibits cell proliferation and promotes cell death. In light of this, we have gathered preliminary evidence testing the efficacy of a chemical compound, an AKT inhibitor for treating leiomyomas in an animal model. We observe that the AKT inhibitor causes significant tissue necrosis in leiomyomas that have been grown in immunocompromised mice. In this proposal, we hypothesize that progesterone can act at both non-genomic (signaling events) as well as genomic (at the gene) levels to promote leiomyoma growth. It does this by targeting the AKT signaling pathway and the downstream effector, FOXOI. Thus, inhibition of this pathway should provide a means of inhibiting leiomyoma growth and promoting tissue death. To test this hypothesis, we propose three aims.
Specific aim 1 will investigate the elucidating the mechanisms that are involved in PR attenuation of FOXOI action on a gene called BM, that is involved in apoptosis (cell death).
Specific aim 2 will explore how progesterone activates the AKT pathway and what the consquence of inhibiting this pathway would be on cell proliferation.
Specific aim 3 investigates the efficacy of the AKT inhibitor in inducing apoptosis in leiomyoma cells as well as human leiomyoma tissues that are growing in immunocompromised mice.

Public Health Relevance

Millions of women in the US are affected by symptomatic uterine leiomyomata causing significant morbidity. The studies in this project explore an important signaling pathway, PI3K/AKT/F0X01, that is activated by progesterone and associated with cell proliferation and survival. This study will provide a potential mechanism of action of PR in promoting growth of leiomyomas and translate these data into a potential treatment nf leiomyomas.; PROJEeT/

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-05
Application #
8495373
Study Section
Special Emphasis Panel (ZHD1-DSR-K)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$219,857
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Marsh, Erica E; Chibber, Shani; Wu, Ju et al. (2016) Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 expression and regulation in uterine leiomyoma. Fertil Steril 105:1070-5
Vidimar, Vania; Gius, David; Chakravarti, Debabrata et al. (2016) Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas. Sci Adv 2:e1601132
Sengoba, Katherine S; Ghant, Marissa S; Okeigwe, Ijeoma et al. (2016) Racial/Ethnic Differences in Women's Experiences with Symptomatic Uterine Fibroids: a Qualitative Assessment. J Racial Ethn Health Disparities :
Marsh, Erica E; Bernardi, Lia A; Steinberg, Marissa L et al. (2016) Novel correlates between antimüllerian hormone and menstrual cycle characteristics in African-American women (23-35 years-old). Fertil Steril 106:443-450.e2
Yin, Ping; Ono, Masanori; Moravek, Molly B et al. (2015) Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J Clin Endocrinol Metab 100:E601-6
Moravek, Molly B; Yin, Ping; Ono, Masanori et al. (2015) Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications. Hum Reprod Update 21:1-12
Childress, Krista J; Lawson, Angela K; Ghant, Marissa S et al. (2015) First contact: the intersection of demographics, knowledge, and appraisal of treatment at the initial infertility visit. Fertil Steril 104:180-7
Bulun, Serdar E; Moravek, Molly B; Yin, Ping et al. (2015) Uterine Leiomyoma Stem Cells: Linking Progesterone to Growth. Semin Reprod Med 33:357-65
Moravek, Molly B; Bulun, Serdar E (2015) Endocrinology of uterine fibroids: steroid hormones, stem cells, and genetic contribution. Curr Opin Obstet Gynecol 27:276-83
Kim, Ji-Young; Banerjee, Taraswi; Vinckevicius, Aurimas et al. (2014) A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. Mol Cell 54:613-25

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