REGULATION OF UTERINE FIBROIDS BY CCN5

CCN5 对子宫肌瘤的调节

基本信息

批准号：
7656064
负责人：
John J Castellot
金额：
$ 34.21万
依托单位：
TUFTS UNIVERSITY BOSTON
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656064
关键词：
Adenovirus Vector Affect Alternative Splicing American Animal Model Area Attention Autologous Basic Science Biochemical Biological Assay Biological Models Biomedical Engineering Blood Vessels Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cell Fractionation Cell Nucleus Cell Proliferation Cell physiology Cells Common Neoplasm Communities Confocal Microscopy Cultured Cells Cyclin D1 Data Digestion Disease Family Fibroid Tumor Functional disorder Gases Gene Cluster Gene Expression Genes Goals Growth Health Care Costs Hemorrhage Human Hysterectomy Immunocompromised Host Implant In Vitro Infertility Knowledge Laboratories Lead Leiomyoma Length Mediating Medical Methodology Methods Molecular Molecular Weight Mus Muscle function Myometrial NOD/SCID mouse Neoplasms Non-Malignant Operative Surgical Procedures Pain Pathogenesis Pathway interactions Patients Peptides Physiological Post-Translational Protein Processing Prevalence Protein Chemistry Proteins Recombinants Recurrence Regulation Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Severities Signal Pathway Signal Transduction Silk Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Stimulation of Cell Proliferation Structure Structure-Activity Relationship Symptoms Testing Therapeutic Therapeutic Uses Translating Uterine Fibroids Uterus Variant Woman Women&apos s Health Work base cell motility cellular engineering design emotional distress experience high throughput screening improved in vivo in vivo Model inhibitor/antagonist insight member mouse model myometrium new therapeutic target novel novel strategies polypeptide prevent protein expression prototype public health relevance research study small molecule tumor uterine smooth muscle cell

项目摘要

DESCRIPTION (provided by applicant): Leiomyomata (fibroids) are a non-malignant neoplasia of uterine smooth muscle cells (UtSMC) that afflict approximately 20% of all women and 80% of black women in the U.S. The most common tumor in women, fibroids cause severe pain and bleeding as well as infertility. Though temporary respite from the symptoms can be achieved by medical and surgical interventions, the only treatment that prevents recurrence is hysterectomy. More than 200,000 hysterectomies are performed annually in the U.S., with direct health care costs exceeding $2B; the emotional distress caused by loss of the uterus is incalculable. Despite its prevalence and severity, this condition has received sparse attention in the basic research community until quite recently. If we are to advance our understanding of the pathogenesis and improve treatment options for fibroids, it is critical to elucidate the mechanisms that underlie UtSMC proliferation. Work in our laboratory showed that the growth-arrest protein CCN5 was nearly absent in human fibroids, yet abundant in the normal myometrium of the same patients. We have also demonstrated that the CCN5 protein blocks human UtSMC proliferation in culture and in animal models by >80%. Gene profiling indicates that CCN5 regulates clusters of genes that control mitogenic signal transduction and cell cycle progression. These observations underpin our central hypothesis that CCN5 has a key role in maintaining normal smooth muscle function in the uterus, and that dysregulation of CCN5 expression is a major factor in the pathogenesis of fibroids. A corollary hypothesis is that administration of CCN5 will reduce or prevent fibroid formation. To test these hypotheses, in this revised proposal we will carry out structure-function analyses to determine the mechanisms by which CCN5 regulates UtSMC function using a combination of in vitro and in vivo model systems. Using immunocompromised mice implanted with human fibroid UtSMC engineered to express CCN5, we will determine if CCN5 or related peptides can suppress fibroid formation. These experiments are designed to provide a comprehensive assessment of the effects of CCN5 in human UtSMC from the molecular to the physiologic and pharmacologic levels. We hope the results of the proposed work will provide new insights into the pathophysiologic role of CCN5 in fibroids, and lead to novel therapeutic targets for treating this important women's health issue. PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate the mechanism of action of the protein CCN5 on uterine leiomyoma cells, and to determine if CCN5 has potential therapeutic value in the treatment of fibroids.

描述（由申请人提供）：平滑肌疗法（肌瘤）是子宫平滑肌细胞（UTSMC）的非机敏性肿瘤（UTSMC），在美国，大约20％的女性和80％的黑人妇女中，妇女中最常见的肿瘤是妇女中最常见的肿瘤，伴有肌动物造成严重的疼痛和出血，并且出血。尽管可以通过医疗和手术干预措施来暂时喘息，但唯一阻止复发的治疗方法是子宫切除术。在美国，每年进行超过200,000个子宫切除术，直接医疗保健费用超过$ 2B；因子宫丧失而造成的情绪困扰是无法估量的。尽管它的盛行和严重程度，但直到最近，这种情况还是在基础研究社区中受到了很少的关注。如果我们要提高对发病机理的理解并改善肌瘤的治疗选择，那么阐明UTSMC增殖的机制至关重要。在我们的实验室中的工作表明，人类肌瘤中几乎没有生长促进蛋白CCN5，但在同一患者的正常子宫肌层中很丰富。我们还证明，CCN5蛋白会阻止培养物中的人类UTSMC增殖，而动物模型则> 80％。基因分析表明，CCN5调节控制有丝分裂信号转导和细胞周期进程的基因簇。这些观察结果基于我们的中心假设，即CCN5在维持正常平滑肌功能中具有关键作用，而CCN5表达的失调是辅助辅酶发病机理的主要因素。推论假设是CCN5的给药将减少或预防肌瘤形成。为了检验这些假设，在此修订的建议中，我们将进行结构功能分析，以确定CCN5使用体外和体内模型系统组合来调节UTSMC功能的机制。使用用于表达CCN5的人肌瘤UTSMC植入的免疫功能低下的小鼠，我们将确定CCN5或相关肽是否可以抑制肌瘤形成。这些实验旨在全面评估CCN5对从分子到生理和药理水平的人类UTSMC的影响。我们希望拟议的工作的结果将为CCN5在肌瘤中的病理生理作用提供新的见解，并为治疗这一重要的女性健康问题带来新的治疗靶标。公共卫生相关性：该项目的目的是阐明蛋白质CCN5对子宫平滑肌瘤细胞的作用机理，并确定CCN5在治疗肌瘤的治疗方面是否具有潜在的治疗价值。