Project 3 for Uterine Leiomyoma Research Center Program

The primary objective of the Program, namely investigating important pathways and nuclear receptors amenable to targeting with currently available or upcoming pharmaceutical compounds leading to development of novel medical management options for uterine leiomyoma within the foreseeable future, will be accomplished under three projects. Project I (PI: Bulun) has been developed to ascertain the mechanisms as to how anti-progestins reduce the size of uterine leiomyomata and significantly improve symptoms such as irregular bleeding. Through genome-wide unbiased approaches, we have identified novel genes and mechanisms that regulate cell proliferation and apoptosis in uterine leiomyoma. We predict that these target genes and mechanisms comprise an important aspect of the pathologic effects of progesterone and therapeutic effects of anti-progestins on uterine leiomyoma. We expect that definition of these mechanisms will lead to more refined treatments targeting specific molecules and producing milder side effects. In addition to tumorigenesis, a unique pathologic aspect of uterine leiomyoma is the excessive formation of extracellular matrix, i.e., fibrosis. Project II which will investigate the novel roles of NR4A subfamily of nuclear receptors and their cross talk with TGFbeta/Smad signaling pathways in cell proliferation and fibrosis will be led by Drs. Chakravarti and Nowak. The definition of these clinically relevant pathways via in vitro and in vivo studies will lead to novel and alternative targets for the management of uterine leiomyoma and clarify another important aspect of NR and TGFbeta signaling in leiomyoma. Drs. Kim and Wei will lead project III……. This project will be pursued to determine the roles of FOXO and AKT signaling pathways in regulating leiomyoma cell growth in relation to PR action. Investigators of this project have uncovered in vivo and in vitro interactions between FOXO1, AKT and PR in leiomyoma smooth muscle cells. This pathway regulates cell growth, and targeting of AKT inhibits cell growth. . Drs. Kim and Wei will direct Project III. During the last funding period, it was demonstrated that the PI3K/AKT pathway is a major growth and survival pathway for leiomyomas and inhibition of AKT promotes mitochondrial disruption, resulting in the downstream induction of permanent growth arrest and cell death. Specifically, we will test novel mechanisms that involve increase of mitochondrial reactive oxygen species, miR182, HMGA2, and BCL2. All three projects are conceptually connected under the umbrella of providing in depth mechanistic analysis and identifying key molecules that drive growth (proliferation and ECM deposition) and survival in order to develop targeted treatments for uterine leiomyoma.