Protein Tyrosine Kinases in Leiomyomata Uteri

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Uterine leiomyomas or flbroids are benign pelvic tumors that originate from uterine cells. The clinically apparent incidence of leiomyoma in women of productive age is about 25%, whereas pathological examination places the rate of incidence as high as 75%. The growth of leiomyoma is dependent on the female sex hormones, estrogen and progesterone. We propose that hormones stimulate the expression and/or activation of protein tyrosine kinases (YK's) to promote the growth of fibroids. This hypothesis predicts that inhibition of YK's involved in the proliferation of uterine cells would halt the growth of fibroids. Therefore, we propose to survey the expression and the activity of YK's in normal uterine myometrium and leiomyomas. We propose to create microarrays that are suitable for profiling the expression of all 90 human YK genes (Aim 1). Using these microarrays, we will profile the expression of YK's in specimens of normal myometrium and leiomyoma procured from patients in different age and ethnic groups because these factors are known to affect the risk for fibroid (Aim 2). In addition to the static view of YK expression profiles in patient samples, we will determine the influence of hormones on YK expression (Aim 3). We will examine the protein levels and kinase activities of YK's that are expressed in normal and fibroid tissues (Aim 4). We will develop the necessary anti-YK and "phospho-specific" antibodies if commercial antibodies are not available. We will disrupt the activity of YK's that are expressed and/or activated in fibroids by small molecule inhibitors, if available; or by siRNA, and then measure the hormone-dependent proliferative response of leiomyomas in athymic nude mice (Aim 5). Results from the proposed study will identify tyrosine kinases that are important for the proliferation of fibroids. Tyrosine kinases have been successfully targeted in the development of rational therapy for human cancers. Information gathered from the proposed research may therefore lead to the development of new therapeutics to control the growth of fibroids.