mTORC1 and WNT in lung mesenchyme

肺间质中的 mTORC1 和 WNT

• 批准号: 10278071
• 负责人: VERA P KRYMSKAYA
• 金额: $ 65.61万
• 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/10278071
• 关键词: AGTR2 gene; AXIN2 gene; Address; Age; Alleles; Alveolar; Animal Genetics; Animal Model; Asthma; Cells; Chronic; 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; Side; Signal Pathway; Sirolimus; Smooth Muscle Myocytes; Structure; TSC1/2 gene; TSC2 gene; Testing; Therapeutic Intervention; Tuberous sclerosis protein complex; 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; 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.

项目概要 淋巴管平滑肌瘤病 (LAM) 是一种罕见的致命性囊性肺病，由双等位基因失活突变引起 结节性硬化症复合体 (TSC1/TSC2) 基因编码雷帕霉素机制靶标的抑制因子 复合物 1 (mTORC1)。 LAM 细胞的起源仍然未知。我们对 LAM 肺与年龄的肺进行了比较 和性别匹配的健康对照肺作为假设生成方法来识别细胞亚型 特定于 LAM。我们的单细胞 RNA 测序分析揭示了新型间充质和移行肺泡 LAM 肺特有的上皮状态。该分析确定了协调 LAM 的间充质细胞中枢 疾病表型。小鼠肺中 Tsc2 的间充质限制性缺失产生 mTORC1 驱动的 肺表型，肺泡结构逐渐破坏，肺功能下降， WNT 配体的增加以及间充质和上皮肺细胞基因中女性特异性的深刻变化 表达。 WNT 信号基因失活可逆转 mTORC1 驱动的肺的年龄依赖性变化 表型，但仅肺间充质中的 WNT 激活不足以形成小鼠 LAM- 像表型。我们的研究确定了 mTORC1 激活的肺中性别和年龄特异性基因变化 间充质并确定 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 LAM 细胞中 mTORC1 过度激活 mTORC1-WNT 信号串扰失调，导致慢性囊性空腔扩大 驻留间充质和肺泡上皮细胞的激活。我们的翻译假设表明 将过度活跃的 mTORC1 和 WNT 信号抑制至基础生理水平代表了一种潜在的 有机会增强雷帕拉类似物的功效，并有可能为 LAM 患者提供新的治疗方法。 为了检验我们的假设，我们将具体询问： 目标 1：LAM 细胞的小子集如何诱导全局 肺的病理变化是以肺间质细胞为中心的吗？目标 2：激活 LAM 肺间充质中的 mTORC1-WNT/β-连环蛋白通路会调节肺泡上皮细胞的适应性吗？目的 3：mTORC1-WNT/β-catenin 通路的联合治疗靶向是否会提供新的治疗方法 LAM 的机会？ 拟议的研究不仅将产生关于 TSC2 依赖的 mTORC1 作用的重要新见解 LAM 中的激活和 WNT 信号传导，同时也加深了我们对 LAM 肺间质细胞如何发挥作用的理解 协调囊性肺损伤。我们的转化研究也可能为治疗提供新策略 针对过度活跃的 mTORC1 和 WNT 信号通路的干预措施，尚未经过测试 LAM 的治疗。