Estrogen Signaling in a Mouse Model for Lymphangioleiomyomatosis

淋巴管平滑肌瘤小鼠模型中的雌激素信号传导

• 批准号: 9189693
• 负责人: STEPHEN R. HAMMES
• 金额: $ 35.16万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-04 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189693
• 关键词: Actins; Affect; Architecture; Aromatase Inhibitors; Biological Markers; Biology; Cell Line; Cell Proliferation; Cells; Characteristics; Contraceptive Usage; Cyst; Data; Dependence; Detection; Development; Differentiation Antigens; Disease; Dissection; Estradiol; Estrogen Receptors; Estrogens; FDA approved; Female; Gelatinase B; Gene Expression; Genes; Goals; Growth; In Vitro; Investigation; Knockout Mice; Knowledge; Laboratories; Leiomyoma; Lesion; Lung; Lung Lymphangioleiomyomatosis; Lung Neoplasms; Lung Transplantation; Lung diseases; Lymphangioleiomyomatosis; Lymphatic; Lymphatic Spread; MMP2 gene; MMP9 gene; Maintenance; Matrix Metalloproteinases; Measures; Mediating; Modeling; Mus; Mutation; Myometrial; Neoplasm Metastasis; Nuclear; Null Lymphocytes; Optics; Oral Contraceptives; Ovariectomy; Pathway interactions; Patients; Peptide Hydrolases; Phosphotransferases; Plethysmography; Pneumothorax; Positioning Attribute; Pregnancy; Prevalence; Progesterone; Progesterone Receptors; Pulmonary function tests; Recurrence; Respiratory Failure; Respiratory physiology; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Staining method; Stains; Steroids; Structure; Suggestion; Techniques; Testing; Therapeutic; Transplantation; Tuberous sclerosis protein complex; Tumor Burden; Tumor Markers; Tumor Suppressor Genes; Up-Regulation; Uterine Fibroids; Uterine Neoplasms; Uterus; Woman; X-Ray Computed Tomography; adenoma; extracellular; fascinate; in vivo; inhibitor/antagonist; knock-down; loss of function; melanocyte; migration; mouse model; myometrium; neoplastic cell; novel; novel strategies; protein expression; public health relevance; pulmonary function; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a somewhat rare but devastating progressive lung disease in which adenomas consisting of immature smooth muscle cells grow within the lungs. As LAM tumors expand, patients develop pulmonary cysts, recurrent pneumothorax, and progressive pulmonary function loss, sometimes requiring lung transplantation. One difficulty in studying LAM, and therefore in developing therapeutic options, has been that the origin of the LAM cell is unknown. However, several features of LAM offer potential clues. First, LAM cells contain inactivating mutations in tumor suppressor genes Tsc1 or Tsc2, leading to increased mTORC1-mediated proliferation. Second, LAM affects almost exclusively women, with a female prevalence of over 99.95%. Third LAM progression is enhanced by estradiol. Finally, LAM lung tumors may be metastatic, as patients who have undergone lung transplantation can develop LAM tumors in transplanted lungs. To explain these LAM characteristics, we proposed that lung LAM cells might be derived from smooth muscle uterine myometrial cells lacking Tsc. In fact, when we ablated Tsc2 in the mouse uterus, we saw myometrial overgrowth, leiomyoma formation, and metastatic myometrial lung tumors. Uterine and lung tumors shared many features of LAM, including increased mTORC1 activity and positive staining for LAM markers. We also found that myometrial tumors expressed high levels and activity of matrix metalloproteinases (MMPs). Notably, tumor growth, mTORC1 activity, melanocyte differentiation marker expression, and protease expression, were almost completely dependent on estradiol, suggestive that estradiol may be a key regulator of LAM. In short, our model confirms a potential metastatic origin of LAM from the uterus, and provides a robust model for LAM. Here we will use our model to: 1) Examine mechanisms of estrogen-dependence using state-of-the art strategies for measuring estradiol, kinase, and mTORC1 signaling; 2) Examine lung damage and function using plethysmography, pulmonary function testing, and CT scanning; and 3) Examine the roles of MMPs in LAM progression as well as the utility of measuring MMP activity as a biomarker for tumor burden using protease-sensitive optical biomarkers. With our team's expertise in steroid signaling, uterine and lung biology, and protease detection, we believe that we are in a unique position to make novel discoveries that will not only help us understand and treat LAM, but will also enhance our general knowledge of how estrogen promotes tumor progression.

 描述（由申请人提供）：淋巴管平滑肌瘤病（LAM）是一种有点罕见但具有破坏性的进行性肺病，其中由不成熟平滑肌细胞组成的腺瘤在肺内生长。随着 LAM 肿瘤的扩大，患者会出现肺囊肿、复发性气胸和进行性肺功能丧失，有时需要肺移植。研究 LAM 以及开发治疗方案的一个困难是 LAM 细胞的起源未知。然而，LAM 的几个特征提供了潜在的线索。首先，LAM 细胞含有肿瘤抑制基因 Tsc1 或 Tsc2 的失活突变，导致 mTORC1 介导的增殖增加。其次，LAM 几乎只影响女性，女性患病率超过 99.95%。雌二醇可增强第三次 LAM 进展。最后，LAM 肺肿瘤可能是转移性的，因为接受肺移植的患者可能会在移植的肺中出现 LAM 肿瘤。为了解释这些 LAM 特征，我们提出肺 LAM 细胞可能源自缺乏 Tsc 的平滑肌子宫肌层细胞。事实上，当我们在小鼠子宫中消融 Tsc2 时，我们看到了肌层过度生长、平滑肌瘤形成和转移性肌层肺肿瘤。子宫和肺部肿瘤具有 LAM 的许多特征，包括 mTORC1 活性增加和 LAM 标记物呈阳性染色。我们还发现子宫肌层肿瘤表达高水平和高活性的基质金属蛋白酶（MMP）。值得注意的是，肿瘤生长、mTORC1 活性、黑素细胞分化标志物表达和蛋白酶表达几乎完全依赖于雌二醇，表明雌二醇可能是 LAM 的关键调节因子。简而言之，我们的模型证实了 LAM 潜在的子宫转移起源，并为 LAM 提供了稳健的模型。在这里，我们将使用我们的模型来：1）使用最先进的测量雌二醇、激酶和 mTORC1 信号传导的策略来检查雌激素依赖性机制； 2）通过体积描记法、肺功能测试和CT扫描检查肺损伤和功能； 3) 检查 MMP 在 LAM 进展中的作用，以及使用蛋白酶敏感的光学生物标志物测量 MMP 活性作为肿瘤负荷生物标志物的效用。凭借我们团队在类固醇信号传导、子宫和肺部生物学以及蛋白酶检测方面的专业知识，我们相信我们处于独特的地位，可以做出新的发现，这不仅有助于我们理解和治疗 LAM，而且还将增强我们对雌激素如何促进肿瘤进展的一般知识。