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（由适用提供）：淋巴血管瘤瘤病（L​​AM）是一种在女性中发现的罕见疾病，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，导致气道限制。该疾病的病因尚不清楚，但被认为涉及荷尔蒙调节，因为它通常在初潮和绝经之间呈现。此外，在结节硬化症复合物（TSC）突变的患者中经常发现LAM，这表明TSC失活会有助于其发育。我们正在通过有条件地删除和/或激活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的病理。我们通过构成激活 - 帕宁蛋白或表达染上腺瘤性息肉病（APC）的截短等位基因来创建了用子宫特异性平瘤（肌瘤）创建的小鼠，我们显示了静脉炎的初步证据表明，静脉体瘤是由于血管造血和后续的超元素而出现的。穆勒式风管衍生的女性生殖道机器人（子宫，卵形，子宫颈和阴道的颅骨部分）是男性双重电位哺乳动物胚胎中唯一的结构，这表明荷尔蒙反应性刺激性的细胞可能是对UTORUS的刺激性细胞的刺激性，是UTORUS的细胞，是UTORUS的Puligon unigon ubonus untrorus unirus ublorian胚胎。林。我们假设肺LAM可能是由子宫血管病变引起的，这些病理允许子宫基质细胞插入，随后可以在肺部产生和增殖。对我们的子宫出血和平滑肌瘤的小鼠模型对肺的组织学分析显示，纤维化肺斑块类似于在人类LAM中观察到的，这些肺斑点也是HMB45-，ASMA-和Desmin阳性的人类LAM的标记。 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 horseone responsiveness of the smooth muscle cells in the lung lesions, and (4) assess the marker profile of Lung lesions for comparison with human LAM.这些研究的结果将为触发器的持续投资和涉及LAM病变发展的信号通路的基础奠定基础，并为针对这些途径的临床前研究提供了体内模型系统。 公共卫生相关性：淋巴管肌瘤病（LAM）研究的主要未知数之一是平滑肌细胞的原始细胞或组织，它们渗入肺部以形成纤维化病变。我们已经在子宫内产生了伤口愈合不良的小鼠，这导致出血，肥厚疤痕和纤维。我们研究肺部的初步结果表明，循环的创伤后子宫细胞可能是引起LAM的细胞。拟议的研究将研究子宫细胞是否是在LAM中发现的纤维化细胞的来源，LAM肺部病变是否具有荷尔蒙反应性，以及这些突变小鼠是否是投资与肺部细胞浸润以及可能治疗性诊断的精确研究的机制和途径所需的模型系统。