mTOR signaling in lung homeostasis, aging and disease

mTOR 信号在肺稳态、衰老和疾病中的作用

• 批准号: 10609457
• 负责人: VERA P KRYMSKAYA
• 金额: $ 48.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609457
• 关键词: Acceleration; Actins; Address; Adjuvant; Affect; Age; Aging; Alleles; Alveolar; Antiestrogen Therapy; Applications Grants; Biomedical Research; Cells; Characteristics; Clinic; Cyst; Data; Diagnosis; Disease; Disease Progression; Epithelium; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; FDA approved; FGF7 gene; FRAP1 gene; Female; Future; Genes; Genetic; Genetic Transcription; Gonadal Steroid Hormones; Homeostasis; Human; Human Characteristics; Lesion; Lung; Lung Lymphangioleiomyomatosis; Lung diseases; Lymphangioleiomyomatosis; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Microscopic; Mission; Modeling; Mus; Mutation; National Heart, Lung, and Blood Institute; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Pneumothorax; Predisposition; Pregnancy; Proteins; Risk; Risk Factors; Role; SDZ RAD; Signal Transduction; Sirolimus; Smooth Muscle; Structure; TSC1/2 gene; TSC2 gene; Tamoxifen; Testing; Therapeutic; Tuberous Sclerosis; Up-Regulation; Woman; Women' s Health; age related; functional decline; gain of function; improved; in vivo; insight; lung lesion; mouse model; novel; novel therapeutic intervention; overexpression; pre-clinical; pulmonary function; pulmonary function decline; sex; side effect

Abstract Uncontrolled activation of the mechanistic target of rapamycin (mTOR) is a cause of pulmonary lymphangioleiomyomatosis (LAM), a predominantly female, rare genetic lung disease triggered by bi-allelic inactivating mutations in the mTOR’s upstream negative regulator the tuberous sclerosis complex (TSC1/TSC2) genes. The loss of TSC2 function and mTOR activation are associated with formation of microscopic smooth muscle-like LAM lesions and lung cysts - leading to spontaneous pneumothoraxes and progressive loss of pulmonary function primarily in women. Our lab pioneered the idea of using mTOR inhibitory drugs for LAM. Unfortunately, targeting mTOR with FDA-approved drugs Sirolimus or Everolimus (rapamycin) only delays the disease progression while causing lasting side effects in up to 60% of women. In addition, even with current treatment, some LAM patients are unresponsive to the rapalogs. Thus, despite significant progress, key unanswered questions remain, including: 1) how do only ~5% of the lung cells, which are bonafide “LAM cells” carrying genetic TSC2 mutations and mTOR activation, promote cystic remodeling of the whole lung? 2) what is the role of estrogen in making LAM a predominantly female disease? and 3) why is the risk of LAM is age- dependent? The objective of this proposal is to test our overarching hypothesis that mTOR activation in LAM cells deregulates their secretome and alters lung mesenchymal-epithelial crosstalk. We will explore whether sex predilection and pregnancies exacerbate these changes accelerating lung function decline in females. Our translational hypothesis states that anti-estrogen therapy represents a potential opportunity for fast tracking this hypothesis to benefit predominantly female LAM patients. The proposed study will yield essential new insights into the role of TSC2-dependent mTOR activation and estrogen on age-dependent lung structure and function with specific focus on a rare, predominantly female lung disease LAM. We will also perform preclinical anti- estrogen studies to explore future prospects for novel adjuvant therapeutic approaches for LAM in clinic.

抽象的 雷帕霉素（MTOR）机械靶靶的不受控制的激活是肺的原因 淋巴血管肌瘤病（LAM）是一种主要是雌性的，罕见的遗传肺疾病 MTOR上游负调节剂中的灭活突变（TSC1/TSC2） 基因。 TSC2功能和MTOR激活的丧失与微观平滑的形成有关 肌肉状的lam病变和肺囊肿 - 导致自发性气胸和逐渐丧失 肺部功能主要在女性中。我们的实验室开创了使用MTOR抑制性药物作为LAM的想法。 不幸的是，用FDA批准的药物Sirolimus或Evelolimus（Rapamycin）靶向MTOR仅延迟 疾病进展，同时在多达60％的女性中造成持久副作用。另外，即使有当前 治疗，一些LAM患者对Rapalogs无反应。那是目的地的重大进展，关键 仍有未解决的问题，包括：1）如何仅约5％的肺部细胞，即真正的“ LAM细胞” 携带遗传TSC2突变和MTOR激活，促进整个肺的囊性重塑？ 2）是什么 雌激素在使LAM成为主要女性疾病中的作用？ 3）为什么lam的风险是年龄的 依赖？ 该提案的目的是检验我们的总体假设，即LAM细胞中MTOR激活 取消了他们的分泌物，并改变了肺间充质 - 上皮串扰。我们将探索性别是否 预测和怀孕加剧了这些变化，使女性的肺功能下降加速。我们的 翻译假设指出，抗雌激素疗法代表了快速跟踪这一点的潜在机会 假设主要受益于女性LAM患者。拟议的研究将产生基本的新见解 TSC2依赖性MTOR激活和雌激素对年龄依赖性肺结构和功能的作用 特别关注罕见的，主要是雌性肺部疾病。我们还将执行临床前抗 雌激素研究探索诊所中LAM的新型可调节治疗方法的未来前景。

项目成果

Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited.

• DOI: 10.1007/s10495-021-01670-4
• 发表时间: 2021-06
• 期刊: Apoptosis : an international journal on programmed cell death
• 作者: Abdelwahab EMM;Bovari-Biri J;Smuk G;Fillinger J;McPhail D;Krymskaya VP;Pongracz JE
• 通讯作者: Pongracz JE

Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.

• DOI: 10.3389/fonc.2021.644592
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Abdelwahab EMM;Bovari-Biri J;Smuk G;Harko T;Fillinger J;Moldvay J;Krymskaya VP;Pongracz JE
• 通讯作者: Pongracz JE