mTOR signaling in lung homeostasis, aging and disease

摘要 雷帕霉素机制靶点（mTOR）的不受控制的激活是肺结核的一个原因。 淋巴管平滑肌瘤病（LAM），一种主要由女性，罕见的遗传性肺部疾病触发的双等位基因 mTOR上游负调节因子结节性硬化症复合体（TSC 1/TSC 2）的失活突变 基因. TSC 2功能的丧失和mTOR活化与显微平滑的细胞膜的形成有关。 肌肉样LAM病变和肺囊肿-导致自发性气胸和进行性肺功能丧失 主要是女性的肺功能。我们的实验室开创了使用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mTOR的表达。 疾病进展，同时在高达60%的女性中引起持久的副作用。此外，即使目前 在治疗中，一些LAM患者对雷帕霉素类似物无反应。因此，尽管取得了重大进展， 仍然存在未解的问题，包括：1）如何只有约5%的肺细胞，这是真正的“LAM细胞” 携带基因TSC 2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）为什么年龄是LAM的风险- 依赖？ 该提议的目的是检验我们的总体假设，即LAM细胞中的mTOR激活 使它们的分泌组失调并改变肺间充质-上皮串扰。我们将探讨性是否 偏好和怀孕加剧了这些变化，加速了女性的肺功能下降。我们 翻译假说指出，抗雌激素治疗代表了一个潜在的机会， 主要受益于女性LAM患者的假设。拟议的研究将产生重要的新见解 TSC 2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，主要是女性肺部疾病LAM。我们还将进行临床前抗- 雌激素研究，以探索临床上LAM新的辅助治疗方法的未来前景。

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.