mTORC1 and WNT in lung mesenchyme

肺间质中的 mTORC1 和 WNT

• 批准号: 10634760
• 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/10634760
• 关键词: AGTR2 gene; AXIN2 gene; Acceleration; 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 Cells; Epithelium; FRAP1 gene; Female; Gene Expression; Genes; Genetic; Growth; Hyperactivity; Knowledge; Lesion; Ligands; Link; Lung; Lung Lymphangioleiomyomatosis; Lung diseases; Lymphangioleiomyomatosis; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular Target; Mus; Mutation; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Pneumothorax; 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; beta catenin; disease phenotype; druggable target; effective therapy; fitness; gain of function; idiopathic pulmonary fibrosis; insight; lung injury; 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 淋巴血管肌瘤病（LAM）是一种罕见的致命囊性肺疾病 结节硬化症复合物（TSC1/TSC2）基因编码雷帕霉素的抑制剂 复合物1（MTORC1）。 LAM细胞的起源仍然未知。与年龄相比 和性匹配的健康对照肺是一种假设生成的方法，以鉴定细胞亚型 特定于林。我们的单细胞RNA测序分析揭示了新型的间充质和过渡性肺泡 上皮状态是Lam Lung独有的。该分析确定了一个间充质细胞轮毂配置LAM 疾病表型。小鼠肺中TSC2的间充质限制缺失产生MTORC1驱动的 肺表型，肺泡结构的逐渐破坏，肺功能下降， Wnt配体的增加以及间质和上皮肺细胞基因的深刻女性特异性变化 表达。 Wnt信号传导的遗传失活会逆转MTORC1驱动的肺的年龄依赖性变化 表型，但在肺间充质中单独激活Wnt不足以发展小鼠LAM- 像表型。我们的研究确定了MTORC1激活的肺的性别和年龄特异性基因的变化 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 失调的MTORC1-WNT信号传导串扰，该信号传导串扰，驱动囊性空域扩大而导致慢性 驻留间充质和肺泡上皮细胞的激活。我们的翻译假设指出 抑制过度活跃MTORC1和WNT信号传导至基础生理水平代表了潜力 增强Rapalogs疗效并有可能为LAM患者提供新疗法的机会。 为了检验我们的假设，我们将在以下方面特别询问：目标1：小部分的小子集如何诱导全局 肺中心的病理变化围绕肺间充质细胞轮毂？目标2：激活 mtorc1-wnt/？ - lam肺间充质中的catenin途径失调肺泡上皮细胞适应性？目的 3：MTORC1-WNT/？ - Catenin途径的治疗靶向将提供新的治疗方法 林的机会？ 拟议的研究不仅将对TSC2依赖性MTORC1的作用产生必不可少的新见解 LAM中的激活和Wnt信号传导，但也提高了我们对LAN肺间充质细胞的理解 编排囊性肺损伤。我们的翻译研究也可能为治疗性提供新颖的策略 靶向多动MTORC1和WNT信号通路的干预措施，尚未测试 林的治疗。

项目成果

Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis.

• DOI: 10.1183/16000617.0100-2023
• 发表时间: 2023-09-30
• 期刊: European respiratory review : an official journal of the European Respiratory Society
• 作者: Evans JF;McCormack FX;Sonenberg N;Krymskaya VP
• 通讯作者: Krymskaya VP