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: 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
• 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' 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

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 雷帕霉素机械靶点 (mTOR) 的不受控制的激活是导致肺部疾病的原因之一。 淋巴管平滑肌瘤病 (LAM)，一种主要由女性引发的罕见遗传性肺部疾病，由双等位基因引发 mTOR 上游负调节因子结节性硬化症复合体 (TSC1/TSC2) 的失活突变 基因。 TSC2 功能的丧失和 mTOR 的激活与微观光滑细胞的形成有关。 肌肉样 LAM 病变和肺囊肿 - 导致自发性气胸和进行性丧失 肺功能主要见于女性。我们的实验室率先提出了使用 mTOR 抑制药物治疗 LAM 的想法。 不幸的是，用 FDA 批准的药物西罗莫司或依维莫司（雷帕霉素）靶向 mTOR 只会延迟 疾病进展，同时对多达 60% 的女性造成持久的副作用。此外，即使当前 在治疗过程中，一些 LAM 患者对雷帕拉同种药物没有反应。因此，尽管取得了重大进展，但关键 尚未解答的问题仍然存在，包括：1）只有约 5% 的肺细胞（真正的“LAM 细胞”）如何发挥作用？ 携带TSC2基因突变和mTOR激活，促进全肺囊性重塑？ 2）什么是 雌激素在使 LAM 成为一种以女性为主的疾病方面有何作用？ 3) 为什么 LAM 的风险是年龄- 依赖？ 该提案的目的是测试我们的总体假设，即 LAM 细胞中 mTOR 激活 解除其分泌组的调节并改变肺间充质-上皮细胞的串扰。我们将探讨性是否 偏爱和怀孕加剧了这些变化，加速了女性肺功能的下降。我们的 转化假说指出，抗雌激素治疗是快速跟踪这一情况的潜在机会 假设主要使女性 LAM 患者受益。拟议的研究将产生重要的新见解 研究 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 特别关注一种罕见的、主要是女性的肺部疾病 LAM。我们还将进行临床前抗 雌激素研究旨在探索临床 LAM 新型辅助治疗方法的未来前景。