Uterine-specific genetic modification and lymphangioleiomyomatosis

描述（由申请人提供）：淋巴管平滑肌瘤病（LAM）是一种罕见疾病，主要见于女性，其特征是肺实质中非典型平滑肌细胞病变弥漫性间质浸润，导致气道受限。该病的病因尚不清楚，但被认为与激素调节有关，因为它通常出现在月经初潮和更年期之间。此外，LAM经常出现在结节性硬化症（TSC）突变的患者中，这表明TSC的失活可能有助于其发展。我们正在通过有条件地删除和/或激活对正常分化和功能至关重要的途径中的候选基因来研究子宫发育和相关病理。我们通过组成性激活-catenin或表达腺瘤性息肉病大肠（APC）的截断等位基因，创造了子宫特异性平滑肌瘤（肌瘤）小鼠，我们已经证明了平滑肌瘤是血管出血和随后的肥厚性瘢痕形成的结果。缪勒管衍生的雌性内部生殖道器官（子宫、输卵管、子宫颈和阴道颅部）是唯一未在雄性双电位哺乳动物胚胎中发现的结构，这表明子宫的激素应答间充质间质细胞可能是肺纤维化细胞的来源，并解释了LAM的女性特异性。我们假设肺LAM可能是由子宫血管病变引起的，子宫血管病变允许子宫间质细胞进入肺部，这些细胞随后可以在肺部停留和增殖。我们的子宫出血和平滑肌瘤小鼠模型的肺组织学分析显示，肺纤维化斑块与人类LAM中观察到的相似，也是HMB45-， aSMA-和desmin阳性，人类LAM的标志物。我们建议进一步研究这一假设，具体目的如下：(1)证实肺病变细胞来源于子宫；(2)确定外周血中是否能检测到子宫间充质细胞；(3)检测肺病变中平滑肌细胞的激素反应性；(4)评估肺病变的标志物谱，与人LAM进行比较。这些研究的结果将为进一步研究LAM病变发展的触发因素和信号通路奠定基础，并为针对这些通路的治疗方法的临床前研究提供体内模型系统。

DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a rare disease primarily found in females and is characterized by a diffuse interstitial infiltrate of atypical smooth muscle cell lesions in the lung parenchyma resulting in airway restriction. The etiology of the disease is unknown but is thought to involve hormonal regulation because it usually presents between menarche and menopause. Additionally, LAM is often found in patients with mutations in tuberous sclerosis complex (TSC), suggesting that inactivation of TSC can contribute to its development. We are studying uterine development and associated pathologies by conditionally deleting and/or activating candidate genes in pathways critical for normal differentiation and function. We have created mice with uterine-specific leiomyomas (fibroids) by either constitutively activating ¿-catenin or by expressing a truncated allele of adenomatous polyposis coli (APC) and we have shown preliminary evidence that the leiomyomas develop as a result of vascular hemorrhaging and subsequent hypertrophic scarring. The Mullerian duct-derived internal female reproductive tract organs (uterus, oviduct, cervix, and cranial portion of the vagina) are the only structures from the bipotential mammalian embryo not found in males, suggesting that the hormonally responsive mesenchymal stromal cells of the uterus might be the source of the cells for pulmonary fibrosis and account for the female-specificity of LAM. We hypothesized that pulmonary LAM might be caused by uterine vascular pathologies that allow intravasation of uterine stromal cells that can subsequently lodge and proliferate in the lungs. Histological analysis of the lungs from our mouse models with uterine hemorrhaging and leiomyomas showed fibrotic lung plaques similar to that observed in human LAM that were also HMB45-, aSMA- and desmin-positive, markers for human LAM. We propose to investigate this hypothesis further with the following Specific Aims: (1) confirm that cells in the lung lesions are derived from the uterus, (2) determine whether uterine mesenchymal cells can be detected in peripheral blood, (3) test the hormone responsiveness of the smooth muscle cells in the lung lesions, and (4) assess the marker profile of lung lesions for comparison with human LAM. The results from these studies will lay the foundation for continued investigation of the triggers and signaling pathways involved in the development of the LAM lesions as well as provide an in vivo model system for preclinical studies of therapeutics targeting those pathways.