mTORC1 and WNT in lung mesenchyme

肺间质中的 mTORC1 和 WNT

• 批准号: 10435544
• 负责人: VERA P KRYMSKAYA
• 金额: $ 61.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435544
• 关键词: AGTR2 gene; AXIN2 gene; Address; Age; Alleles; Alveolar; Animal Genetics; Animal Model; Asthma; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical Trials; Code; Complex; Data; Disease; Epithelial; Epithelial Cells; FRAP1 gene; Female; Gene Expression; Genes; Genetic; Growth; Hyperactivity; Knowledge; Lesion; Ligands; Link; Lung; Lung Lymphangioleiomyomatosis; Lung diseases; Lymphangioleiomyomatosis; Mediating; Mesenchymal; Mesenchyme; Modeling; Mus; Mutation; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Population; Predisposition; Pulmonary Pathology; Role; SDZ RAD; Signal Pathway; Sirolimus; Smooth Muscle Myocytes; Structure; TSC1/2 gene; TSC2 gene; Testing; Therapeutic Intervention; Tuberous Sclerosis; WNT Signaling Pathway; Woman; age related; alveolar epithelium; base; beta catenin; disease phenotype; druggable target; effective therapy; fitness; gain of function; idiopathic pulmonary fibrosis; insight; lung injury; molecular targeted therapies; mouse development; mouse model; novel; novel therapeutic intervention; novel therapeutics; pulmonary arterial hypertension; pulmonary function; sex; side effect; single-cell RNA sequencing; therapeutic target; transcription factor; translational study

Project Summary Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. We profiled a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM- like phenotype. Our study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype. Based on these data, we propose to test our hypothesis that mTORC1 hyperactivation in LAM cells dysregulates mTORC1-WNT signaling crosstalk which drives cystic airspace enlargement due to chronic activation of resident mesenchymal and alveolar epithelial cells. Our translational hypothesis states that dampening hyperactive mTORC1 and WNT signaling to basal physiological levels represents a potential opportunity to enhance the efficacy of rapalogs and potentially provide novel therapy for LAM patients. To test our hypothesis, we will specifically ask in: Aim 1: How does the small subset of LAM cells induce global pathological changes in the lung centered around lung mesenchymal cell hub? Aim 2: Does activation of mTORC1-WNT/?-catenin pathways in LAM lung mesenchyme dysregulate alveolar epithelial cell fitness? Aim 3: Will combined therapeutic targeting of the mTORC1-WNT/?-catenin pathways provide new treatment opportunities for LAM? The proposed studies will yield not only essential new insights into the role of TSC2-dependent mTORC1 activation and WNT signaling in LAM but also advance our understanding of how LAM lung mesenchymal cells orchestrate cystic lung damage. Our translational studies may also provide novel strategies for therapeutic intervention targeting hyperactive mTORC1 and WNT signaling pathways, which have not been tested for treatment of LAM.

项目摘要 淋巴管肌瘤病(LAM)是一种罕见的致死性囊性肺疾病，由双等位基因失活突变引起 结节性硬化症复合体(TSC1/TSC2)基因编码的雷帕霉素机制靶点抑制物 复合体1(MTORC1)。LAM细胞的起源尚不清楚。我们对比了一个林肺的年龄- 和性别匹配的健康对照肺作为一种假说生成方法来识别 具体到林。我们的单细胞RNA测序分析显示了新的间充质和移行肺泡 上皮样状态为林肺所特有。这一分析确定了协调LAM的间充质细胞中枢 疾病表型。小鼠肺组织中间充质受限的TSC2缺失产生mTORC1驱动的 肺表型，肺泡结构进行性破坏，肺功能下降， WNT配体增加，间充质和上皮肺细胞基因发生女性特有的深刻变化 表情。WNT信号的遗传失活逆转mTORC1驱动的肺的年龄依赖性变化 表型，但仅在肺间充质中激活WNT不足以促进小鼠LAM-1的发育。 就像表型一样。我们的研究确定了mTORC1激活的肺中性别和年龄特异性的基因变化 并证实了WNT信号通路在mTORC1驱动的肺中的重要性 表型。 基于这些数据，我们建议检验我们的假设，即在LAM细胞中mTORC1超激活 失调mTORC1-WNT信号串扰，导致慢性阻塞性肺疾病导致囊性空域扩大 驻留间充质和肺泡上皮细胞的激活。我们的翻译假说指出 抑制过度活跃的mTORC1和WNT信号到基础生理水平代表了一种潜在的 有机会提高拉帕洛格的疗效，并有可能为LAM患者提供新的治疗方法。 为了验证我们的假设，我们将特别问：目标1：LAM细胞的一小部分如何诱导全局 以肺间充质细胞中枢为中心的肺部病变？目标2：激活 MTORC1-WNT/？-连环蛋白通路在LAM肺间充质中调节肺泡上皮细胞适合性？目标 3：mTORC1-WNT/？-catenin通路的联合靶向治疗是否会提供新的治疗方法 对林来说有机会吗？ 拟议的研究不仅将对依赖TSC2的mTORC1的作用产生重要的新见解 LAM中的激活和WNT信号转导也促进了我们对LAM肺间充质细胞如何 造成囊性肺损伤。我们的翻译研究也可能为治疗提供新的策略 针对过度活跃的mTORC1和WNT信号通路的干预，这些信号通路尚未进行测试 对林的治疗。