Role of TDP-43 in cellular stress responses

哺乳动物细胞具有多种机制来介导细胞从生理和环境应激中恢复。根据所遇到的压力的类型，可以激活多种信号传导途径，导致从增殖到生长停滞、衰老或细胞死亡的反应。在细胞水平上，对应激的直接反应是形成称为应激颗粒的细胞质结构。应激颗粒含有多种大的蛋白质复合物，它们协同维持mRNA处于沉默状态。我们最近鉴定的一种蛋白质是TAR DNA结合蛋白（TDP-43），它是应激颗粒的组成部分。TDP-43是RNA结合蛋白大家族的成员，称为异质核核糖核蛋白（hnRNP），其中一些已被报道参与细胞应激反应。该研究计划旨在确定TDP-43在细胞应激反应中的作用。该提案结合了各种细胞生物学，生物化学和质谱方法。参加该计划的研究生将获得这些方法以及数据分析的多样化培训。通过TDP-43了解应激颗粒信号传导和动力学将对细胞对生理和环境刺激的反应产生广泛的影响。

Mammalian cells possess a variety of mechanisms to mediate a cell's recovery from physiological and environmental stresses. Depending on the type of stress encountered, a variety of signaling pathways can be activated resulting in responses ranging from proliferation to growth arrest, senescence, or cell death. At the cellular level, the immediate response to a stress is the formation of cytoplasmic structures called stress granules. Stress granules contain a variety of large protein complexes which cooperatively maintain mRNAs in a silent state. One protein we have recently identified as being a component of stress granules is TAR DNA binding protein (TDP-43). TDP-43 is a member of a large family of RNA binding proteins known as heterogeneous nuclear ribonucleoproteins (hnRNPs), some of which have been reported to participate in cellular stress responses. The proposed research program aims to define the role of TDP-43 in cellular stress responses. The proposal incorporates a variety of cell biology, biochemistry and mass spectrometry approaches. Graduate students participating in this program will gain a diversified training in these methods as well as data analysis. Understanding stress granule signaling and dynamics via TDP-43 will have wide-reaching implications for cellular responses to physiological and environmental stimuli.