Uterine-specific genetic modification and lymphangioleiomyomatosis

子宫特异性基因改造和淋巴管平滑肌瘤病

• 批准号: 8177522
• 负责人: JOSE M. TEIXEIRA
• 金额: $ 24.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177522
• 关键词: Accounting; Adenomatous Polyposis Coli; Affect; Alleles; Biological Models; Blood Circulation; Blood Vessels; Breeding; Candidate Disease Gene; Cells; Cephalic; Cervix Uteri; Chronic; Contraceptive Usage; Critical Pathways; Desmin; Detection; Development; Diffuse; Disease; Disease Progression; Embryo; Estradiol; Estrogens; Etiology; Female; Female of child bearing age; Fibroid Tumor; Fibrosis; Fluorescence; Foundations; Functional disorder; Future; Genes; Genetic; Hemorrhage; Hormone Responsive; Hormones; Human; Human Characteristics; Hypertrophic Cicatrix; Immunofluorescence Immunologic; Incidence; Infiltration; Injection of therapeutic agent; Investigation; Lead; Leiomyoma; Lesion; Lung; Lung Lymphangioleiomyomatosis; Lung Transplantation; Lymphangioleiomyomatosis; Malignant Neoplasms; Mammalian Oviducts; Menarche; Menopause; Mesenchymal; Mesenchyme; Modeling; Modification; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Neoplasm Metastasis; Organ; Ovarian Steroid Hormone; Pathology; Pathway interactions; Patient observation; Patients; Process; Progesterone; Progestins; Proliferating; Pulmonary Fibrosis; Rare Diseases; Regulation; Reporter; Research; Respiratory Failure; Signal Pathway; Site; Smooth Muscle; Smooth Muscle Myocytes; Source; Specificity; Stromal Cells; Structure; Structure of paramesonephric duct; Structure of parenchyma of lung; Tail; Testing; Therapeutic Intervention; Tissues; Tuberous Sclerosis; Tuberous sclerosis protein complex; Uterine Fibroids; Uterine Lesion; Uterine hemorrhage; Uterus; Vagina; Veins; Wound Healing; base; cohort; hormone regulation; human TSC1 protein; human TSC2 protein; in vivo Model; interstitial; male; mouse model; mutant; peripheral blood; pill; preclinical study; repaired; reproductive; research study; therapeutic target

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. PUBLIC HEALTH RELEVANCE: One of the major unknowns in lymphangioleiomyomatosis (LAM) research is the cell or tissue of origin for the smooth muscle cells that infiltrate the lung to form the fibrotic lesions. We have generated mice with defective wound healing in uteri, which results in hemorrhaging, hypertrophic scarring and fibroids. Our preliminary results investigating the lungs suggest that circulating post-traumatic uterine cells might be the cells that cause LAM. The proposed studies will investigate whether the uterine cells are the source of fibrotic cells found in LAM, whether the LAM lung lesions are hormonally responsive, and whether these mutant mice will be a needed model system for investing the mechanisms and pathways involved in the infiltration of the lungs with fibrotic cells and for preclinical studies of possible therapeutic intervention.

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的弥漫性间质浸润，导致气道受限。该疾病的病因尚不清楚。被认为涉及激素调节，因为它通常出现在初潮和更年期之间。此外，LAM 常见于患有结节性硬化症突变的患者。 （TSC），表明 TSC 失活有助于其发育。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学。 （肌瘤）通过组成性激活 ¿ -连环蛋白或通过表达腺瘤性息肉病大肠杆菌（APC）的截短等位基因，我们已经显示出平滑肌瘤是由于血管出血和随后的肥厚性疤痕而形成的结果。 、子宫颈和阴道的颅骨部分）是双能哺乳动物胚胎中唯一未在雄性中发现的结构，这表明子宫的激素反应性间充质基质细胞可能是肺纤维化的细胞来源，并解释了 LAM 的女性特异性。我们重新认识到，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基质细胞内渗，从而导致肺纤维化。随后在肺部停留并增殖。对患有子宫出血和平滑肌瘤的小鼠模型的肺部进行组织学分析，结果显示肺部纤维化。与在人类 LAM 中观察到的斑块类似，这些斑块也是 HMB45、aSMA 和结蛋白阳性，是人类 LAM 的标记物。我们建议进一步研究这一假设，具体目标如下：(1) 确认肺部病变中的细胞是。来自子宫，（2）确定外周血中是否可以检测到子宫间充质细胞，（3）测试肺部病变中平滑肌细胞的激素反应性，以及（4）评估肺部病变的标志物谱以进行比较这些研究的结果将为继续研究参与 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的临床前研究提供体内模型系统。 公共卫生相关性：淋巴管平滑肌瘤病 (LAM) 研究的主要未知数之一是平滑肌细胞浸润肺部形成纤维化病变的细胞或组织来源。我们培育了子宫内伤口愈合有缺陷的小鼠。我们对肺部的初步调查结果表明，循环的创伤后子宫细胞可能是导致 LAM 的细胞。拟议的研究将包括子宫细胞是否是 LAM 中发现的纤维化细胞的来源，LAM 肺部病变是否具有激素反应性，以及这些突变小鼠是否是研究肺部浸润机制和途径所需的模型系统。纤维化细胞以及可能的治疗干预的临床前研究。