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Protein Tyrosine Kinases in Leiomyomata Uteri

子宫平滑肌瘤中的蛋白酪氨酸激酶

基本信息

批准号：
7271837
负责人：
JEAN Y.J. WANG
金额：
$ 36.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-26 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7271837
关键词：
Affect Age Antibodies Benign Cell Proliferation Cells DNA Development Disruption Doctor of Philosophy Dyes Estrogens Ethnic group Exons Female Fibroid Tumor Fluorescence Gene Transfer Genes Genomics Glass Goals Gonadal Steroid Hormones Growth Histocytochemistry Hormones Human Human Genome Hysterectomy Incidence Label Lead Leiomyoma Malignant Neoplasms Measures Methods Molecular Profiling Nude Mice Patients Pelvis Phospho-Specific Antibodies Phosphotransferases Phosphotyrosine Progesterone Protein Tyrosine Kinase Proteins Quality Control RNA Rate Research Risk Sampling Slide Small Interfering RNA Specimen Spottings Surveys Therapeutic Intervention Tissues Tumor-Derived Tyrosine Uterine Fibroids Uterus Woman information gathering inhibitor/antagonist myometrium novel therapeutics preference research study response retroviral-mediated small molecule tumor tumor growth

项目摘要

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.

描述（由申请人提供）：子宫肌瘤或肌瘤是起源于子宫细胞的良性盆腔肿瘤。育龄妇女子宫肌瘤临床表观发病率约为25%，而病理检查发病率高达75%。平滑肌瘤的生长依赖于女性性激素、雌激素和黄体酮。我们建议激素刺激蛋白酪氨酸激酶（YK）的表达和/或激活以促进肌瘤的生长。该假说预测，抑制参与子宫细胞增殖的 YK 将阻止肌瘤的生长。因此，我们建议调查YK在正常子宫肌层和平滑肌瘤中的表达和活性。我们建议创建适合分析所有 90 种人类 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群体的患者获得的正常子宫肌层和平滑肌瘤标本中 YK 的表达，因为已知这些因素会影响肌瘤的风险（目标 2）。除了患者样本中 YK 表达谱的静态视图之外，我们还将确定激素对 YK 表达的影响（目标 3）。我们将检查在正常组织和肌瘤组织中表达的 YK 的蛋白质水平和激酶活性（目标 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。如果有的话，我们将通过小分子抑制剂破坏肌瘤中表达和/或激活的 YK 活性；或通过 siRNA，然后测量无胸腺裸鼠中平滑肌瘤的激素依赖性增殖反应（目标 5）。拟议研究的结果将确定对肌瘤增殖很重要的酪氨酸激酶。酪氨酸激酶已成功地成为人类癌症合理疗法开发的目标。因此，从拟议的研究中收集的信息可能会导致开发新的疗法来控制肌瘤的生长。