Leiomyoma (Uterine fibroids) is a major disease that affects women but remains shockingly understudied with few nonsurgical therapeutic options. Leiomyoma is characterized by excessive deposition of extracellular matrix and enhanced proliferation and tumorigenesis of uterine smooth muscle cells. The roles of estrogen and progesterone and their nuclear receptors (NRs) and transforming growth factor ???TGF???signaling in leiomyoma are well established. However, the broader role of the nuclear receptor superfamily and their cross talk with TGF? signaling pathways in leiomyoma remain as some of the major unanswered questions. The long-term goal of this project is to establish systematically the roles of nuclear receptors (NRs) and their ligands and to understand how TGF? signaling is altered in leiomyoma. The goal of this project is to determine the novel roles of NR4A subfamily members, including NR4A1 (NGF1B), NR4A2 (NURR1), and NR4A3 (NOR1) in leiomyoma. We performed expression profiling of leiomyoma tissues and adjacent normal myometrium for all 48 human NRs and demonstrated severe deficiency of the NR4A subfamily members, including NR4A1 (NGF1B), NR4A2 (NURR1), and NR4A3 (NOR1), in leiomyoma. Our preliminary results show that NR4A functions by regulating expression of key profibrotic factors such as TGF?3 and SMAD3 and key extracellular matrix components such as collagen 1A1. Furthermore, NR4As regulate proliferation of leiomyoma primary smooth muscle cells. We hypothesize that the NR4A family of nuclear receptors plays critical and integrative roles involving TGF?? and SMAD signaling in leiomyoma development by regulating key proliferation and profibrotic genes.
The specific aims are:
Specific Aim 1 : Determine how NR4A and TGF?? /SMAD signaling pathways interact to regulate pro-fibrotic genes in leiomyoma.
Specific Aim 2 : Determine the roles of NR4As and their selective modulators in leiomyoma cell proliferation in vitro and tumorigenesis in vivo. The proposed aims will advance our knowledge of this highly prevalent public health challenge for which treatment options are currently limited at best. The proposed work is scientifically, translationally, and clinically significant because it provides a new perspective on and better understanding of the mechanisms underlying leiomyoma development and opens up possibilities for identifying additional therapeutic targets and strategies. It is innovative because it represents the first systematic exploration of previously unrealized roles of the NR4A nuclear receptor family in leiomyoma biology.

Public Health Relevance

Contact PD/PI: BULUN, SERDAR, E PROJECT NARRATIVE ? NOT COMPLETED Per instructions in PAR-13-257 (?Do not complete?) no Project Narrative section has been included. This page is included because the NIH ASSIST system is requiring the Project Narrative component be uploaded. Project Narrative Page 251

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-08
Application #
9351189
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2009-08-15
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Xu, Xiuhua; Kim, J Julie; Li, Yinuo et al. (2018) Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma. J Mol Med (Berl) 96:1095-1106
Zhang, Qing; Kanis, Margaux Jenna; Ubago, Julianne et al. (2018) The selected biomarker analysis in 5 types of uterine smooth muscle tumors. Hum Pathol 76:17-27
Zhang, Qing; Poropatich, Kate; Ubago, Julianne et al. (2018) Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. Int J Gynecol Pathol 37:421-430
Ikhena, Deborah E; Liu, Shimeng; Kujawa, Stacy et al. (2018) RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth. J Clin Endocrinol Metab 103:1842-1849
Ikhena, Deborah E; Bulun, Serdar E (2018) Literature Review on the Role of Uterine Fibroids in Endometrial Function. Reprod Sci 25:635-643
Vidimar, Vania; Chakravarti, Debabrata; Bulun, Serdar E et al. (2018) The AKT/BCL-2 Axis Mediates Survival of Uterine Leiomyoma in a Novel 3D Spheroid Model. Endocrinology 159:1453-1462
Xie, Jia; Xu, Xiuhua; Yin, Ping et al. (2018) Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma. Lab Invest 98:1575-1587
Xie, Jia; Ubango, Julianne; Ban, Yanli et al. (2018) Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations. Genes Chromosomes Cancer 57:485-494
Park, Min Ju; Shen, Hailian; Spaeth, Jason M et al. (2018) Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. J Biol Chem 293:4870-4882
Liu, Shimeng; Yin, Ping; Kujawa, Stacy A et al. (2018) Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma. Oncogene :

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