Regulation of Autophagy and Apoptosis in B lymphocytes

B 淋巴细胞自噬和凋亡的调节

• 批准号: 234605336
• 负责人: Professor Dr. Björn Stork
• 金额: --
• 依托单位: Institut für Molekulare Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234605336?language=en
• 关键词: Regulation; Autophagy; Apoptosis; lymphocytes

The central objective of this proposal is the in-depth analysis of autophagic and apoptotic pathways in B lymphocytes downstream of the B cell antigen receptor (BCR) and CD20. Autophagy is a cellular degradation process which occurs constitutively at basal levels and which appears to fulfil specific functions in B lymphocytes. In turn, the clonal deletion of B lymphocytes with non- or autoreactive antigen receptors plays an important role during B cell development. It has been shown that both processes can be induced by crosslinking the B cell antigen receptor. However, BCR-proximal events remain largely unknown for both cell fate pathways. Next to the analysis of BCR-dependent signal transduction pathways, we will investigate the signalling downstream of the B cell-specific surface molecule CD20, which is the target of monoclonal antibodies used for the treatment of B cell-derived neoplasias and antibody-mediated autoimmune diseases. In addition to the analysis of specific signalling pathways, we also want to characterise the spatial and temporal dynamics of these cell fate decisions downstream of the BCR and CD20. The resulting findings should collectively lead to a better understanding of the mechanisms that regulate B cell homeostasis and that lead to the establishment of central tolerance. Ultimately, we hope to optimise current therapies of B cell-associated diseases by the targeted modulation of autophagic pathways.

该提案的中心目标是深入分析B细胞抗原受体（BCR）和CD 20下游B淋巴细胞中的自噬和凋亡途径。自噬是一种细胞降解过程，其在基础水平上组成性发生，并且似乎在B淋巴细胞中发挥特定功能。反过来，具有非反应性或自身反应性抗原受体的B淋巴细胞的克隆缺失在B细胞发育过程中起重要作用。已经表明，这两个过程可以通过交联B细胞抗原受体来诱导。然而，BCR近端事件在很大程度上仍然是未知的两个细胞命运途径。在分析BCR依赖性信号转导途径之后，我们将研究B细胞特异性表面分子CD 20下游的信号传导，CD 20是用于治疗B细胞源性肿瘤和抗体介导的自身免疫性疾病的单克隆抗体的靶点。除了分析特定的信号通路外，我们还希望研究BCR和CD20下游这些细胞命运决定的空间和时间动态。这些结果将使我们更好地理解调节B细胞稳态和建立中枢耐受性的机制。最终，我们希望通过靶向调节自噬途径来优化目前B细胞相关疾病的治疗。

项目成果

Study of ULK1 Catalytic Activity and Its Regulation.

ULK1催化活性及其调控研究

• DOI: 10.1016/bs.mie.2016.09.067
• 发表时间: 2017
• 期刊: Methods in enzymology
• 作者: Stork B;Dengjel J
• 通讯作者: Dengjel J

Targeting urothelial carcinoma cells by combining cisplatin with a specific inhibitor of the autophagy-inducing class III PtdIns3K complex.

• DOI: 10.1016/j.urolonc.2017.11.021
• 发表时间: 2017-12
• 期刊: Urologic oncology
• 作者: David Schlütermann;M. Skowron;N. Berleth;P. Böhler;J. Deitersen;Fabian Stuhldreier;Nora Wallot-Hieke;Wenxian Wu;C. Peter;M. Hoffmann;G. Niegisch;B. Stork