Estrogen Signaling in a Mouse Model for Lymphangioleiomyomatosis

 描述（由申请人提供）：淋巴管平滑肌瘤病（LAM）是一种较为罕见但破坏性的进行性肺部疾病，其中由未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的一个困难，因此在开发治疗方案中，LAM细胞的起源是未知的。然而，LAM的几个特征提供了潜在的线索。首先，LAM细胞在肿瘤抑制基因Tsc 1或Tsc 2中含有失活突变，导致mTORC 1介导的增殖增加。其次，LAM几乎完全影响女性，女性患病率超过99.95%。第三次LAM进展被雌二醇增强。最后，LAM肺肿瘤可能是转移性的，因为经历肺移植的患者可以在移植的肺中发展LAM肿瘤。为了解释这些LAM特征，我们提出肺LAM细胞可能来源于缺乏Tsc的子宫平滑肌细胞。事实上，当我们消融小鼠子宫中的Tsc 2时，我们看到子宫肌层过度生长、平滑肌瘤形成和转移性子宫肌层肺肿瘤。子宫和肺肿瘤具有LAM的许多特征，包括mTORC 1活性增加和LAM标记物阳性染色。我们还发现，子宫肌层肿瘤表达高水平和活性的基质金属蛋白酶（MMPs）。值得注意的是，肿瘤生长、mTORC 1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，我们的模型证实了子宫LAM的潜在转移来源，并为LAM提供了一个强大的模型。在这里，我们将使用我们的模型：1）检查雌激素依赖的机制，使用最先进的战略，测量雌二醇，激酶，和mTORC 1信号传导; 2）检查肺损伤和功能，使用体积描记术，肺功能测试，和CT扫描;和3）检查MMP在LAM进展中的作用以及使用蛋白酶-免疫组织化学法测量MMP活性作为肿瘤负荷的生物标志物的效用。敏感的光学生物标记物。凭借我们团队在类固醇信号传导，子宫和肺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位置，可以做出新的发现，不仅有助于我们了解和治疗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。

 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.