Protein Tyrosine Kinases in Leiomyomata Uteri

描述(申请人提供)：子宫肌瘤或子宫肌样瘤是起源于子宫细胞的良性盆腔肿瘤。在育龄妇女中，临床上子宫肌瘤的明显发病率约为25%，而病理检查的发病率高达75%。子宫肌瘤的生长依赖于女性性激素、雌激素和孕激素。我们认为激素刺激蛋白酪氨酸激酶(YK‘s)的表达和/或激活，从而促进肌瘤的生长。这一假说预测，抑制YK参与子宫细胞的增殖将阻止肌瘤的生长。因此，我们建议研究YK‘s在正常子宫肌层和子宫肌瘤中的表达和活性。我们建议创建适合于分析所有90个人类YK基因表达的微阵列(目标1)。使用这些微阵列，我们将分析从不同年龄和种族的患者获得的正常子宫肌层和肌瘤标本中YK的表达情况，因为这些因素已知会影响子宫肌瘤的风险(目标2)。除了静态观察患者样本中的YK表达谱外，我们还将确定激素对YK表达的影响(目标3)。我们将检测在正常组织和肌瘤组织中表达的YK的蛋白水平和激酶活性(目标4)。如果没有商业化的抗体，我们将开发必要的抗YK抗体和“磷酸特异性”抗体。我们将干扰在肌瘤中表达和/或激活的YK的活性，如果有小分子抑制剂的话；或者通过siRNA，然后测量裸鼠子宫肌瘤的激素依赖性增殖反应(AIM 5)。这项拟议研究的结果将确定对肌瘤增殖至关重要的酪氨酸激酶。酪氨酸激酶已被成功地用于开发合理的人类癌症治疗方法。因此，从拟议研究中收集的信息可能会导致开发新的治疗方法来控制肌瘤的生长。

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.