Identification and functional characterization of new components of TOR signalling in C. elegans

线虫 TOR 信号传导新成分的鉴定和功能表征

• 批准号: 77821350
• 负责人: Privatdozentin Dr. Elke Neumann-Haefelin
• 金额: --
• 依托单位: Institut für Biologie III
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/77821350?language=en
• 关键词: Identification; functional; characterization; new; components

Upregulation of mammalian target of rapamycin (mTOR) activity has been implicated in polycystic kidney disease and inhibition of the mTOR pathway has been shown to decrease cyst size in animal models and humans. The TOR protein complex 1 (T0RC1) has a central role in cystogenesis, but the upstream pathways linking ciliary signalling to mTOR activation are poorly understood. The T0RC1 pathway promotes growth and cell proliferation in response to amino acids and hormone-dependent signalling in all higher eukaryotes. Inhibition of TORC1 in C. elegans results in developmental arrest as dauer-Iike larvae and increases lifespan in the adult worm. We have established proteome-wide screening methods and identified potential new interactors of Rheb. Preliminary results suggest that TSC/Rheb does not only control TORC1 signalling but may also impinge on signalling pathways important for control of cell cycle and proliferation. Here, we propose to employ the strength of C. elegans to perform genetic analyses, and to characterize newly identified components that regulate or effect TORC1 signalling at the genetic level. This proposal will contribute to a better understanding of the complexity and cross-talks of TOR signalling during development and its role in cystogenesis.

哺乳动物雷帕霉素靶点 (mTOR) 活性的上调与多囊肾病有关，而抑制 mTOR 通路已被证明可以减小动物模型和人类的囊肿大小。 TOR 蛋白复合物 1 (T0RC1) 在囊肿发生中发挥核心作用，但将纤毛信号转导与 mTOR 激活联系起来的上游途径却知之甚少。 T0RC1 通路响应所有高等真核生物中的氨基酸和激素依赖性信号传导，促进生长和细胞增殖。在线虫中抑制 TORC1 会导致 dauer 样幼虫发育停滞，并延长成虫的寿命。我们已经建立了全蛋白质组筛选方法并鉴定了 Rheb 潜在的新相互作用子。初步结果表明，TSC/Rheb 不仅控制 TORC1 信号传导，还可能影响对控制细胞周期和增殖很重要的信号传导途径。在这里，我们建议利用秀丽隐杆线虫的优势进行遗传分析，并表征新发现的在遗传水平上调节或影响 TORC1 信号传导的成分。该提案将有助于更好地理解发育过程中 TOR 信号传导的复杂性和串扰及其在囊肿发生中的作用。

项目成果

A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation

• DOI: 10.1126/scisignal.2002469
• 发表时间: 2012-03-27
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Pezze, Piero Dalle;Sonntag, Annika G.;Thedieck, Kathrin
• 通讯作者: Thedieck, Kathrin

TORC2 signaling antagonizes SKN-1 to induce C. elegans mesendodermal embryonic development.

• DOI: 10.1016/j.ydbio.2013.08.011
• 发表时间: 2013-12-15
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Ruf, Vanessa;Holzem, Christina;Peyman, Tobias;Walz, Gerd;Blackwell, T. Keith;Neumann-Haefelin, Elke
• 通讯作者: Neumann-Haefelin, Elke