BAX/BAK control ER-mitochondria apoptotic crosstalk

描述（由申请人提供）：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稳态起关键调节作用。自体反应性或受损淋巴细胞的清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。BCL-2家族的两个促凋亡成员Bax/Bak双缺陷（DKO）小鼠已经产生并在子宫内大量死亡。DKO小鼠胚胎成纤维细胞或重组成Rag-1 /-小鼠的胎源淋巴细胞对多种死亡刺激（包括特异性靶向内质网（ER）的信号）具有显著的凋亡抗性。虽然最初表明BAX/BAK通过在线粒体中接收活化的BH3蛋白起作用，但初步研究强烈表明，BAX/BAK在维持内质网Ca2+储存和控制内质网和线粒体之间的Ca2+信号传导方面起着第二作用。基于这些结果，本研究旨在了解BAX/BAK如何控制ER Ca2+储存，以及这在线粒体依赖性细胞凋亡的调节中起什么作用。

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.