Uterine Leiomyoma Development in Mouse Models

小鼠模型中子宫肌瘤的发育

基本信息

批准号：
9277297
负责人：
JOSE M. TEIXEIRA
金额：
$ 35.34万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277297
关键词：
Affect African American Age Alleles American Anti-Mullerian Hormone Receptor Type II Benign Binding Biological Assay Cell Polarity Cell Proliferation Cells Characteristics Clonality Common Neoplasm Deposition Development Dimerization Disease Estrogen Receptor alpha Etiology Exhibits Extracellular Matrix FRAP1 gene Fascicle Female Female infertility Fibroid Tumor Fibrosis Frequencies Functional disorder Gene Expression Genes Genetic Transcription Growth and Development function Healthcare High Prevalence Histologic Homeostasis Hormonal Change Human Human Characteristics Hysterectomy In Vitro Incidence Infertility Knock-in Leiomyoma Lesion LoxP-flanked allele Mediating Mesenchymal Mesenchyme Microscopic Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Myofibroblast Myometrial Nuclear Operative Surgical Procedures Organ Pain Pathogenesis Pathologic Pathway Analysis Pathway interactions Patients Pelvic Pain Penetrance Periodicity Peutz-Jeghers Syndrome Phenotype Prevalence Property Proto-Oncogene Proteins c-akt Rattus Regulation Reproduction S-Phase Fraction STK11 gene Signal Transduction Smooth Muscle Myocytes Smooth Muscle Tumor Source Symptoms TSC1 gene Therapeutic Intervention Time Tissues Transforming Growth Factor beta Tuberous Sclerosis Uterine Fibroids Uterine Neoplasms Uterine hemorrhage Uterus WNT Signaling Pathway Woman adenylate kinase beta catenin care burden cis acting element cofactor dimer human female in vivo insight mTOR Signaling Pathway malformation mouse model mutant mutant mouse model myometrium novel therapeutics preclinical study promoter public health relevance reproductive reproductive tract response steroid hormone targeted treatment therapeutic target transcriptome sequencing treatment strategy tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Uterine fibroids (leiomyomata uteri) are the most common tumors in the female reproductive tract. Some estimates indicate that more than 50% of American women have uterine fibroids. Additionally, there is a significant disparity in the incidence of fibroids since African-American women are 2-3 times more likely to develop fibroids. These tumors can be very painful and are a leading cause of infertility in women. Also, because these tumors can become very large, and although the uterus is indispensable for mammalian reproduction, they remain the main reason for hysterectomies in the US. Despite the healthcare burden caused by uterine fibroids, their etiology and pathophysiology are unknown. We have developed mutant mice in which nuclear ß-catenin signaling has been specifically induced in reproductive tract tissues. Normally, mice do not develop fibroids; however, these mutant mice develop smooth muscle tumors in their uteri with 100% penetrance by 8 weeks of age. These tumors exhibit characteristics of human fibroids by histological and immunohistochemical criteria. ß-Catenin, a well-known downstream effector of Wnt signaling, induces organ and tissue malformations and tumor development following dysregulation of its activity. The mice also express higher levels of mTor, as observed in the Tsc2-mutant Eker rat fibroid model and in approximately 50% of human fibroids, suggesting that mTor activation may be a common pathway in leiomyoma development. We will investigate this mouse model further, placing particular emphasis on the regulation of mTor gene expression and activity for comparison with other mutant mouse models lacking myometrial Lkb1, the gene mutated in patients with Peutz-Jeghers Syndrome, and Tsc1, both of which also induce mTor activity and induce uterine fibroids as shown in our preliminary results. We propose to investigate the intracellular mechanisms and pathways affected by dysregulated Wnt/ß-catenin in our unique mouse model that induce mTor activity for comparison with Lkb1- and Tsc2-deleted uteri. To better understand the etiology and pathogenesis of fibroids, we will study the molecular mechanisms controlling fibrosis in the mutant myometrial cells such as cell polarity, extracellular matrix deposition, and myometrial differentiation. We will determine which characteristics of the mouse models most closely resemble human leiomyomas and are best suited for preclinical studies. Lastly, we will determine whether disrupted Wnt/ß-catenin signaling contributes to human leiomyoma development. The results from the studies in this proposal will provide new insights into the etiology and progression of these tumors, as well as provide the rationale for investigating therapies targeting the mechanisms involved in leiomyoma development and progression.

描述（由申请人提供）：子宫肌瘤（子宫平滑肌瘤）是女性生殖道中最常见的肿瘤。一些估计表明，超过 50% 的美国女性患有子宫肌瘤。此外，子宫肌瘤的发病率也存在显着差异。肌瘤，因为非裔美国女性患肌瘤的可能性是女性的 2-3 倍。这些肿瘤可能会非常疼痛，并且是导致女性不孕的主要原因。因为这些肿瘤可能变得非常大，尽管子宫对于哺乳动物的繁殖是不可或缺的，但它们仍然是美国子宫切除术的主要原因，尽管子宫肌瘤造成了医疗负担，但其病因和病理生理学尚不清楚。其中，核β-连环蛋白信号在生殖道组织中被特异性诱导，正常情况下，小鼠不会出现肌瘤；然而，这些突变小鼠的子宫中会出现平滑肌肿瘤。根据组织学和免疫组织化学标准，这些肿瘤在 8 周龄时外显率达到 100%。 β-Catenin 是一种著名的 Wnt 信号传导下游效应物，其活性失调后会诱导器官和组织畸形和肿瘤发展。正如在 Tsc2 突变 Eker 大鼠肌瘤模型和大约 50% 的人类肌瘤中观察到的那样，小鼠还表达了更高水平的 mTor，这表明mTor 激活可能是平滑肌瘤发展的常见途径，我们将进一步研究该小鼠模型，特别强调 mTor 基因表达和活性的调节，以便与缺乏子宫肌层 Lkb1（该基因在黑斑息肉患者中发生突变）的其他突变小鼠模型进行比较。 Jeghers 综合征和 Tsc1，两者也会诱导 mTor 活性并诱导子宫肌瘤，如我们的初步结果所示，我们建议研究受失调影响的细胞内机制和途径。我们独特的小鼠模型中的 Wnt/ß-连环蛋白可诱导 mTor 活性，以便与 Lkb1 和 Tsc2 缺失的子宫进行比较。为了更好地了解子宫肌瘤的病因和发病机制，我们将研究控制突变子宫肌细胞纤维化的分子机制，例如细胞极性，细胞外我们将确定小鼠模型的哪些特征最接近人类平滑肌瘤并且最适合临床前研究，最后我们将确定破坏的 Wnt/β-连环蛋白信号是否有助于人类平滑肌瘤的发展。该提案中的研究将为这些肿瘤的病因和进展提供新的见解，并为研究针对平滑肌瘤发生和进展机制的疗法提供依据。