mTOR信号通路在垂体瘤发生发展中的作用及机制

As one of the most common intracranial tumors, pituitary tumor is associated with high morbidity. Effective therapeutics are currently not available for many pituitary tumor patients due to the largely undefined pathological processes of pituitary tumorigenesis. We found hyperactivation of mechanastic Target of Rapamycin (mTOR) in both estrogen induced rat pituitary tumor and human pituitary tumor samples, while inhibition of mTOR signaling blocked estrogen mediated pituitary tumor formation in the rat model. This promopted us to study the role of mTOR signaling in pituitary tumorigenesis. We identified that upregulation of pituitary tumor transforming gene 1 (PTTG1) is necessary for mTOR mediated xenograft tumor development in nude mice. Therefore we propose that hyperactivation of mTOR promotes pituitary tumorigenesis through upregulation of PTTG1 and targeted suppression of mTOR or PTTG1 may be used in the treatment of pituitary tumors. To test this hypothesis, we will first generate a mouse pituitary tumor model by deletion of mTOR suppressor Tsc1 in the pituitary gland. Pttg1 conditional knockout mice will be generated and cross-mated with Tsc1 conditional knockout mice. It is anticipated that Pttg1 depletion should eradicate the pituitary tumors caused by mTOR activation. This project may provide insight into the role and mechanism of mTOR signaling in pituitary tumor development and the prove-of-concept for inhibition of mTOR and its effectors in the treatment of pituitary tumor. This mouse model may also serve as a platform for the study and drug development of pituitary tumor.

垂体瘤是一严重影响患者健康的常见颅内肿瘤，缺乏相应的动物模型，其发病机理不明确，药物治疗效果有限。我们前期发现，人垂体瘤组织中雷帕霉素靶蛋白（mTOR）通路异常活化，mTOR抑制剂可以阻断雌激素诱导的大鼠垂体瘤的发生发展，mTOR活化可以上调垂体瘤转化基因1（PTTG1）而促进肿瘤细胞在裸鼠皮下成瘤，提示mTOR功能亢进对垂体瘤起重要作用。我们假设mTOR可通过上调PTTG1促进垂体瘤的发生发展，抑制mTOR或PTTG1等下游通路有助于垂体瘤的治疗。我们拟通过垂体特异性敲除mTOR上游抑制基因Tsc1建立小鼠垂体瘤模型,预期抑制mTOR或敲除Pttg1基因可以阻碍垂体瘤的形成。本研究的实施将有助于阐明mTOR通路在垂体腺瘤发生中的作用和机理，并提供垂体瘤治疗的新策略，该垂体瘤模型还可成为药物筛选的平台。

垂体瘤是一严重影响患者健康的常见颅内肿瘤，缺乏相应的动物模型，其发病机理不明确，药物治疗效果有限。我们发现，人垂体瘤组织中雷帕霉素靶蛋白（mTOR）通路异常活化，mTOR抑制剂rapamycin可以阻断雌激素诱导的大鼠垂体瘤的发生发展，分别垂体特异性敲除mTOR上游抑制基因Tsc1或Pten导致小鼠发生垂体瘤, 而用rapamycin抑制mTOR阻碍垂体瘤的形成，mTOR活化上调垂体瘤转化基因1（PTTG1）促进肿瘤细胞成瘤。本研究说明mTOR功能亢进对垂体瘤起重要作用，mTOR可通过上调PTTG1促进垂体瘤的发生发展，抑制mTOR或PTTG1等下游通路有助于垂体瘤的治疗。本项目成功构建的二种垂体瘤模型还可成为今后药物筛选的平台。