mTOR signaling in lung homeostasis, aging and disease

mTOR 信号在肺稳态、衰老和疾病中的作用

基本信息

批准号：
10163904
负责人：
VERA P KRYMSKAYA
金额：
$ 48.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163904
关键词：
Acceleration Address Adjuvant Affect Age Aging Alleles Alveolar Antiestrogen Therapy Applications Grants Biomedical Research Cells Characteristics Clinic Cyst Data Diagnosis Disease Disease Progression Epithelial Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogens FDA approved FGF7 gene FRAP1 gene Female Future 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 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 protein complex Up-Regulation Woman Women&apos s Health age related alpha Actin functional decline gain of function improved in vivo insight male mouse model novel novel therapeutic intervention overexpression pre-clinical pulmonary function pulmonary function decline sex side effect

项目摘要

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，关键尚未解决的问题仍然存在，包括：1）如何仅约5％的肺细胞，它们是真正的“ 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。