Leiomyomas are benign uterine tumors dependent on ovarian steroids for their growth. Through genomics and proteomics we have identified a number of differentially expressed and regulated genes in leiomyomas with diverse biological functions, including cellular transformation, proliferation, apoptosis and proinflammatory/pro-fibrotic activities. The expression of some of these genes is regulated by ovarian steroids through ER/PR genomic and non-genomic pathways. MicroRNAs (miRNAs) are novel class of small non- protein coding RNAs which regulate the stability of target gene expression through repression and degradation. We have identified the expression of a number of miRNAs in paired myometrium and leiomyomas and their isolated smooth muscle cells (MSMC and LSMC), including miR-18a, 21, 181a,142-5p and 542-3p, predicted to target the expression of ERs, PR, GPR30 and proinflammatory/profibrotic genes, respectively. Furthermore, the expression ofgenes, which collectively play a central role in pathogenesis of leiomyoma. Our core hypothesis is that the expression of these miRNAs displays a specific pattern during leiomyomas growth and regression, and their regulation by ovarian steroids represents a mechanism that precedes their actions on target genes, thus influencing the outcome of multiple cellular activities critical to leiomyomas growth. To test this hypothesis Aim #1 will assess the expression of miR-18a, 21, 181a, 142-5p and 542-3p and their predicted target genes encoding ERs, PR, GPR30, IL-13, TGF-2, FBLN4, FMOD, MMP7 and TIMP-3 in paired myometrium and leiomyoma during growth (proliferative and secretory phases of the menstrual cycle) and regression (GnRHa therapy) based on ethnicity. Utilizing gene microarray profiles previously obtained for paired leiomyoma and myometrium, we will identify and determine functional annotation of these miRNAs overall target genes.
Aim #2 will assess the regulatory function of ovariagonists, respectively. To achieve our aims, we will utilize a combination of biochemical, molecular and cell biological approaches. We anticipate that the information gained from these studies leads to identification of a novel molecular mechanism directed by miRNAs resulting in regulation of specific genes whose products play a central role in leiomyoma growth and regression, permitting work toward development of a novel therapeutic to control their growth.
Fibroids are benign uterine tumors estimated to develop in 70% of women during their reproductive years, with symptomatic tumors causing chronic pelvic pain and abnormal uterine bleeding. This proposal will investigate how fibroids grow and ways to prevent their symptoms and growth.
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|Chegini, Nasser (2010) Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder. Semin Reprod Med 28:180-203|