Pathobiology Of Uterine Leiomyomas (fibroids)

子宫平滑肌瘤（肌瘤）的病理学

• 批准号: 8929703
• 负责人: DARLENE DIXON
• 金额: $ 212.98万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8929703
• 关键词: Address; Affect; Apoptosis; Apoptosis Regulator; Archives; Biological; Biological Models; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Treatment; Development; Diethylstilbestrol; Disease; Environmental Risk Factor; Exposure to; Extracellular Matrix; Fibroid Tumor; Genistein; Goals; Growth; Growth Factor; Growth Factor Receptors; Hormonal; Hormones; Housing; Human; Leiomyoma; Ligands; Mitotic Activity; Molecular; Mus; Myometrial; Pathogenesis; Pathway interactions; Patients; Pesticides; Phytoestrogens; Play; Premenopause; Prevention strategy; Production; Receptor Protein-Tyrosine Kinases; Research; Risk Factors; Rodent; Role; Sampling; Signal Pathway; Staging; Telomerase; Therapeutic Intervention; Tissue Sample; Tissues; Treatment Protocols; Uterine Fibroids; Uterus; Woman; carcinogenesis; cell growth; disorder prevention; environmental agent; fenvalerate; human tissue; in vitro Model; myometrium; neonatal exposure; overexpression; prenatal exposure; proliferative phase Menstrual cycle; prospective; reproductive; tumor; tumor growth; tumorigenesis

The Molecular Pathogenesis Group has focused much of its research on defining the pathogenesis of disorders affecting the reproductive tract of humans and rodents and assessing the role of environmental and endogenous hormones, and growth factors on the growth and induction of these disorders. In understating the role of proliferation in human uterine leiomyoma (fibroid) growth, we have found that both positive and negative regulators of apoptosis are not differentially expressed in fibroids compared to normal myometria, and that altered apoptosis does not appear to play a significant role in the development of these tumors. Our studies show that cell proliferation and extracellular matrix production may be the most significant contributors to fibroid growth, although, mitotic activity of fibroid cells appears to be phasic, does not correlate with tumor size, and is autonomous for each tumor within a uterus. In studies addressing the role of growth factors in the pathogenesis of fibroids, we have found that Receptor Tyrosine Kinases (RTKs) and their ligands are overexpressed in fibroids compared to normal myometria during the proliferative phase of the menstrual cycle and that the many of the RTKs are activated. These studies will help to define some of the basic biological and molecular pathways important in fibroid growth, which can then be applied to developing alternative noninvasive treatment regimens for fibroids. In vitro model systems for studying fibroids are limited in that human derived leiomyoma cells grow poorly in culture. We have overcome this obstacle by development of hTERT (human telomerase) immortalized uterine leiomyoma and myometrial cell lines. These cells are being used to study leiomyoma tumorigenesis in a prospective manner. In determining the role of environmental agents in fibroid development we have found that in CD-1 mice prenatal and neonatal exposures to diethylstilbestrol (DES) results in uterine leiomyomas similar to fibroids observed in women. Also, the phytoestrogen, genistein, can be stimulatory or inhibitory to uterine leiomyoma cell growth depending on its concentration. We have also found that an environmental pesticide, Fenvalerate, can induce cell proliferation and extracellular matrix production in uterine leiomyoma and myometrial cells, and may be a potential risk factor for fibroids.

分子发病机组的大部分研究集中在定义影响人类和啮齿动物生殖道的疾病的发病机理上，并评估环境和内源激素的作用，以及生长因子对这些疾病的生长和诱导的作用。在低估了增殖在人子宫平滑肌瘤（肌瘤）生长中的作用时，我们发现与正常肌分立相比，凋亡的正和阴性调节剂在肌瘤中均未差异表达，而凋亡的改变似乎在这些肿瘤的发育中似乎并不重要。我们的研究表明，细胞增殖和细胞外基质产生可能是肌瘤生长的最重要的促成因素，尽管肌瘤细胞的有丝分裂活性似乎是阶段性的，与肿瘤的大小无关，并且对于子宫内的每个肿瘤都是自主的。在解决生长因子在肌瘤发病机理中的作用的研究中，我们发现受体酪氨酸激酶（RTKS）及其配体在男性循环的增殖阶段与正常肌谱相比在肌瘤中过表达，并且许多RTK被激活。这些研究将有助于定义一些在肌瘤生长中重要的基本生物学和分子途径，然后将其应用于开发肌瘤的替代性非侵入性治疗方案。用于研究肌瘤的体外模型系统受到限制，因为人类衍生的平滑肌瘤细胞在培养中生长较差。我们通过发展HTERT（人端粒酶）永生的子宫平滑肌瘤和肌层细胞系来克服这一障碍。这些细胞用于以前瞻性方式研究肿瘤的平滑肌瘤。在确定环境药物在肌瘤发育中的作用时，我们发现，在CD-1小鼠中，对二乙基苯甲酸酯（DES）的新生儿暴露会导致类似于女性观察到的肌瘤的子宫平滑肌瘤。同样，根据其浓度，植物雌激素，染料木黄酮可以刺激性或抑制性子宫平滑肌瘤的生长。我们还发现，环境农药（Fenvalerate）可以在子宫平滑肌瘤和肌层细胞中诱导细胞增殖和细胞外基质产生，并且可能是辅助肌瘤的潜在危险因素。