Protein Tyrosine Kinases in Leiomyomata Uteri

子宫平滑肌瘤中的蛋白酪氨酸激酶

• 批准号: 7114921
• 负责人: JEAN Y.J. WANG
• 金额: $ 37.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114921
• 关键词: age difference; athymic mouse; cell line; cell proliferation; clinical research; female; gene expression; human middle age (35-64); human subject; immunocytochemistry; leiomyoma; microarray technology; myometrium; polymerase chain reaction; protein tyrosine kinase; racial /ethnic difference; small interfering RNA; tissue /cell culture; uterus; women' s health; young adult human (21-34)

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.

描述（由申请人提供）：子宫平滑肌瘤或肌瘤是起源于子宫细胞的盆腔良性肿瘤。在育龄妇女中，平滑肌瘤的临床发病率约为25%，而病理检查显示其发病率高达75%。平滑肌瘤的生长依赖于女性性激素，雌激素和黄体酮。我们提出激素刺激蛋白酪氨酸激酶（YK's）的表达和/或激活来促进肌瘤的生长。这一假说预测，抑制参与子宫细胞增殖的YK会阻止肌瘤的生长。因此，我们拟探讨YK在正常子宫肌层和子宫平滑肌瘤中的表达和活性。我们建议创建适合分析所有90个人类YK基因表达的微阵列（目的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瘤和平滑肌瘤标本中YK的表达，因为已知这些因素会影响肌瘤的风险（目的2）。除了患者样本中YK表达谱的静态视图外，我们还将确定激素对YK表达的影响（目的3）。我们将检查正常组织和肌瘤组织中表达的YK的蛋白水平和激酶活性（目的4）。如果没有商业抗体，我们将开发必要的抗yk和“磷酸特异性”抗体。如果可用，我们将通过小分子抑制剂破坏在肌瘤中表达和/或激活的YK的活性；或通过siRNA，然后在胸腺裸鼠中测量平滑肌瘤的激素依赖性增殖反应（Aim 5）。该研究的结果将确定酪氨酸激酶对肌瘤的增殖是重要的。酪氨酸激酶已经成功地用于人类癌症的合理治疗。因此，从拟议的研究中收集的信息可能会导致新的治疗方法的发展，以控制肌瘤的生长。