mTOR signaling in lung homeostasis, aging and disease

摘要 雷帕霉素(MTOR)机械靶点的失控激活是肺损伤的原因之一 淋巴管肌瘤病(LAM)，一种以女性为主的罕见遗传性肺部疾病，由双等位基因引发 MTOR上游负调控因子结节性硬化症复合体(TSC1/TSC2)的失活突变 基因。TSC2功能丧失和mTOR激活与微观光滑的形成有关 肌样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，FDA批准的药物西罗莫司或埃博利莫斯(雷帕霉素)靶向mTOR只会推迟 在疾病进展的同时，高达60%的女性会产生持久的副作用。此外，即使在当前 在治疗过程中，一些LAM患者对拉帕罗格没有反应。因此，尽管取得了重大进展，但关键是 仍然没有答案的问题包括：1)为什么只有~5%的肺细胞是真正的“LAM细胞” 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成为以女性为主的疾病中所起的作用？3)为什么LAM的风险是年龄- 依赖？ 这项提议的目的是测试我们的总体假设，即在LAM细胞中mTOR激活 解除对其分泌体的控制，改变肺间充质-上皮间充质-上皮串扰。我们将探索性行为是否 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 翻译假说指出，抗雌激素治疗代表着快速追踪这一点的潜在机会。 假设主要惠及女性LAM患者。拟议的研究将产生重要的新见解 TSC2依赖的mTOR激活和雌激素对年龄依赖性肺结构和功能的影响 特别关注一种罕见的、以女性为主的肺部疾病LAM。我们还将进行临床前的抗病毒治疗 雌激素研究，探索LAM临床新的辅助治疗方法的前景。

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.