BAX/BAK control ER-mitochondria apoptotic crosstalk

描述(申请人提供)：细胞凋亡，或程序性细胞死亡，是细胞自杀的一种生理形式，对免疫系统的发育和动态平衡起关键调节作用。自我反应或受损淋巴细胞的去除缺陷被认为会导致自身免疫性疾病和白血病/淋巴瘤。因此，了解参与淋巴细胞凋亡的信号通路仍然是一个重要的挑战。BAX/BAK(DKO)双缺陷小鼠是bcl2家族的两个促凋亡成员，已经产生，并且大部分在子宫中死亡。重组为RAG-1-/-小鼠的dKO小鼠胚胎成纤维细胞或胎儿来源的淋巴细胞对多种死亡刺激，包括针对内质网(ER)的信号，具有显著的抗凋亡能力。虽然最初的研究表明，Bax/BAK是通过在线粒体上接收激活的BH3蛋白来发挥作用的，但初步研究表明，Bax/BAK在维持ER钙储存和控制ER和线粒体之间的钙信号转导方面发挥了第二个作用。基于这些结果，本研究旨在了解Bax/BAK是如何控制内质网钙离子储存的，以及这在线粒体依赖性细胞凋亡的调控中起到什么作用。 具体地说，该项目的目的是：1)确定内质网衍生的钙离子在成纤维细胞细胞死亡中的作用；2)确定促凋亡的Bax/BAK调节内质网和线粒体之间的钙信号的机制；3)确定Bax/BAK缺乏如何影响T淋巴细胞中的钙依赖信号。进一步的工作将确定免疫系统中控制细胞死亡的信号通路，以从根本上了解自身免疫和癌症的发病机制。 首席研究员斯科特·奥克斯博士是医学博士，已完成解剖病理学住院医师培训，希望发展一项独立的研究生涯，专注于细胞凋亡的分子途径及其与人类疾病的关系。赞助商斯坦利·J·科斯迈尔博士是细胞凋亡领域的世界领先者，在培训成功的基础研究人员方面有着良好的记录。

DESCRIPTION (provided by applicant): Apoptosis, or programmed cell death, is a physiological form of cell suicide that critically regulates the development and homeostasis of the immune system. Defects in the removal of self-reactive or damaged lymphocytes are thought to lead to autoimmune disease and leukemia/lymphoma. Therefore, understanding the signaling pathways involved in lymphocyte apoptosis remains an important challenge. Mice doubly-deficient in Bax/Bak (DKO), two proapoptotic BCL-2 family members, have been generated and largely die in utero. DKO mouse embryonic fibroblasts or fetal-derived lymphocytes reconstituted into Rag-1-/- mice are strikingly resistant to apoptosis in response to a wide range of death stimuli, including signals specifically targeting the endoplasmic reticulum (ER). While originally shown to work by receiving activated BH3 proteins at mitochondria, preliminary studies strongly suggest that BAX/BAK play a second role in maintaining ER Ca2+ stores and controlling Ca2+ signaling between the ER and mitochondria. Based on these results, this proposal intends to understand how BAX/BAK control ER Ca2+ stores and what role this plays in their regulation of mitochondrial-dependent apoptosis. Specifically, the project aims to: 1) Define the contribution of ER-derived Ca2+ in cell death in fibroblasts, 2) Determine the mechanism by which proapoptotic BAX/BAK regulate Ca2+ signaling between ER and mitochondria, and 3) Determine how BAX/BAK deficiency affects Ca2+-dependent signaling in T lymphocytes. Further work will define the signaling pathways controlling cell death in the immune system to gain fundamental insight into the pathogenesis of autoimmunity and cancer. Dr. Scott Oakes, the Principal Investigator, is an M.D., who has completed residency training in anatomic pathology, and wishes to develop an independent research career focusing on the molecular pathways of apoptosis and how they relate to human disease. The sponsor, Dr. Stanley J. Korsmeyer, is a world-leader in the field of apoptosis with a strong record of training successful basic investigators.