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：
8439082
负责人：
JOSE M. TEIXEIRA
金额：
$ 38.38万
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/8439082
关键词：
Accounting 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 Disease Etiology Exhibits Extracellular Matrix Fascicle Female Fibroid Tumor Fibrosis Frequencies Functional disorder Gene Expression Genes Growth and Development function Healthcare High Prevalence Homeostasis Hormonal Change Human Human Characteristics Hysterectomy In Vitro Incidence Infertility Leiomyoma Lesion Mediating Mesenchymal Mesenchyme Microscopic Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Myofibroblast Myometrial Nuclear Operative Surgical Procedures Organ Pain Pathogenesis Pathway interactions Patients Pelvic Pain Penetrance Peutz-Jeghers Syndrome Phenotype Prevalence Property Proto-Oncogene Proteins c-akt Rattus Regulation Reproduction STK11 gene Signal Pathway Signal Transduction Smooth Muscle Myocytes Smooth Muscle Tumor Source Symptoms Therapeutic Intervention Time Tissues Tuberous Sclerosis Uterine Fibroids Uterine Neoplasms Uterine hemorrhage Uterus Woman adenylate kinase care burden cis acting element cofactor dimer human female in vitro activity in vivo indexing insight mTOR protein malformation mouse model mutant mutant mouse model myometrium novel therapeutics preclinical study promoter public health relevance reproductive response steroid hormone 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 ¿-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. ¿-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/¿-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/¿-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 ¿连环蛋白信号传导在生殖道组织中被特异性诱导。通常，小鼠不会出现肌瘤；然而，这些突变小鼠在 8 周龄时会在子宫中出现平滑肌肿瘤，且外显率达到 100%。这些肿瘤表现出人类肌瘤的特征。组织学和免疫组织化学标准。 -Catenin 是一种众所周知的 Wnt 信号传导下游效应子，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 突变型 Eker 大鼠肌瘤模型和大约 10 例中观察到的，小鼠还表达较高水平的 mTor。 50% 的人类肌瘤，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。与其他缺乏子宫肌层 Lkb1（黑斑息肉综合征患者基因突变）和 Tsc1 的突变小鼠模型进行比较，如我们的初步结果所示，这两种基因也诱导 mTor 活性并诱导子宫肌瘤。 Wnt/¿ 失调影响通路-catenin 在我们独特的小鼠模型中诱导 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、细胞外的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 Wnt/¿ -连环蛋白信号传导有助于人类平滑肌瘤的发展。本提案中的研究结果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展和进展机制的治疗提供依据。