Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women. The overall incidenced of leiomyomas may be as high as 70-75% while the rate of symptomatic leiomyomas in women ranges from 25-60%. However, available treatments for leiomyomas are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are still not well understood. Two essential features of leiomyoma tumors are an increase in smooth muscle cell proliferation and excessive extracellular matrix (ECM) deposition. Thus leiomyomas display characteristics similar to other fibrotic diseases such as keloids and renal fibrosis. Changes in production of ECM proteins, particularly collagen, cause profound changes in proliferation and differentiation of smooth muscle cells or fibroblast cells. Recent studies have shown that collagen can act in concert with various growth factors to regulate proliferation of these cells. We hypothesize that the increased proliferation exhibited by leiomyoma cells is due to a major shift in the ECM environment caused by increased synthesis of new, monomeric collagen by these cells. We also hypothesize the antifibrotic drugs that inhibit collagen production may be effective treatments for leiomyomas.
The specific aims of this proposal are: 1) To determine whether changes in collagen production by leiomyoma SMCs regulate proliferation by altering interactions between growth factor receptors and integrins. Our goal is to determine whether the antiproliferative effect of antifibrotic drugs is dependent on a decrease in newly synthesized collagen and whether this alters tyrosine kinase receptor signaling;2) To determine whether alterations in collagen production by leiomyoma SMCs regulate progression of these cells through the cell cycle and induce apoptosis by blocking the AKT signaling pathway. This will be addressed using siRNA and adenoviral infection approaches to block components of the AICT signaling pathway;3) To determinen the efficacy of the antifibrotic drug halofuginone as a treatment for leiomyomas in an in vivo animal model for leiomyomas, the Eker rat.

Public Health Relevance

The results of the proposed studies will provide new insights into how changes in the extracellular matrix environment contribute to the growth of leiomyomas through regulation of cell proliferation or cell death. Most importantly, these studies will have significant clinical relevance as they may lead to the identification of a new group of drugs as potential therapeutic agents for treatment of leiomyomas.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-04
Application #
8382610
Study Section
Special Emphasis Panel (ZHD1-DSR-K)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$333,414
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Bernardi, Lia A; Carnethon, Mercedes R; de Chavez, Peter J et al. (2017) Relationship between obesity and anti-Müllerian hormone in reproductive-aged African American women. Obesity (Silver Spring) 25:229-235
Sengoba, Katherine S; Ghant, Marissa S; Okeigwe, Ijeoma et al. (2017) Racial/Ethnic Differences in Women's Experiences with Symptomatic Uterine Fibroids: a Qualitative Assessment. J Racial Ethn Health Disparities 4:178-183
Zhang, Qing; Poropatich, Kate; Ubago, Julianne et al. (2017) Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. Int J Gynecol Pathol :
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
Ubago, Julianne M; Zhang, Qing; Kim, Julie J et al. (2016) Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis. Am J Surg Pathol 40:923-33
Marsh, Erica E; Steinberg, Marissa L; Parker, J Brandon et al. (2016) Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production. Fertil Steril 106:766-72
Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L et al. (2016) Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model. Hum Reprod 31:1540-51
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
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

Showing the most recent 10 out of 42 publications