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 淋巴管平滑肌瘤病（LAM）是一种罕见的致命性囊性肺病，由于双等位基因失活突变， 编码雷帕霉素机制靶点抑制因子的结节性硬化症复合体（TSC 1/TSC 2）基因 复合物1（mTORC 1）。LAM细胞的起源仍然未知。我们分析了一个林肺的年龄- 和性别匹配的健康对照肺作为一种产生假设的方法，以确定细胞亚型， 具体到LAM。我们的单细胞RNA测序分析揭示了新的间充质和过渡性肺泡 LAM肺特有的上皮状态。该分析鉴定了协调LAM的间充质细胞枢纽。 疾病表型小鼠肺中Tsc 2的间质限制性缺失产生mTORC 1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，以及间充质和上皮肺细胞基因的显著女性特异性变化 表情WNT信号转导的基因失活逆转mTORC 1驱动的肺的年龄依赖性变化 表型，但肺间质中单独的WNT活化不足以发展小鼠LAM-1。 类似的表型。我们的研究确定了mTORC 1激活的肺中性别和年龄特异性的基因变化 间充质细胞，并建立了mTORC 1驱动的肺中WNT信号通路的重要性 表型 基于这些数据，我们提出测试我们的假设，即在LAM细胞中mTORC 1过度激活 mTORC 1-WNT信号传导串扰失调，其驱动由于慢性炎症引起的囊腔扩大。 激活驻留的间充质和肺泡上皮细胞。我们的翻译假说指出， 将过度活跃的mTORC 1和WNT信号传导抑制到基础生理水平代表了一种潜在的 这是增强雷帕霉素类似物的疗效并可能为LAM患者提供新疗法的机会。 为了验证我们的假设，我们将具体地问：目标1：LAM细胞的小子集如何诱导全局 以肺间充质细胞中心为中心的肺部病理变化？目标2：激活 mTORC1-WNT/？- LAM肺间充质中的连环蛋白通路失调肺泡上皮细胞适应性？目的 3：将mTORC 1-WNT/？-连环蛋白通路提供了新的治疗方法 机会来了，林？ 拟议的研究不仅将产生对TSC 2依赖性mTORC 1作用的重要新见解， 激活和WNT信号转导，而且还促进了我们对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mTORC 1和WNT信号通路的干预措施尚未经过测试 治疗LAM。

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