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，其关键性地调节免疫系统的发育和稳态。自身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。Bax/巴克（DKO）是BCL-2家族的两个促凋亡成员，其双缺陷小鼠已经产生，并且大部分在子宫内死亡。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响应于广泛的死亡刺激（包括特异性靶向内质网（ER）的信号）而对细胞凋亡具有显著抗性。虽然最初显示通过在线粒体处接收活化的BH 3蛋白而起作用，但初步研究强烈表明BAX/巴克在维持ER Ca 2+储存和控制ER与线粒体之间的Ca 2+信号传导中发挥第二作用。基于这些结果，本建议旨在了解BAX/巴克如何控制ER Ca 2+商店，以及这在其调节细胞依赖性凋亡中起什么作用。 具体而言，该项目旨在：1）确定ER衍生的Ca 2+在成纤维细胞中细胞死亡的贡献，2）确定促凋亡BAX/巴克调节ER和线粒体之间Ca 2+信号传导的机制，3）确定BAX/巴克缺乏如何影响T淋巴细胞中的Ca 2+依赖性信号传导。进一步的工作将确定控制免疫系统中细胞死亡的信号通路，以获得对自身免疫和癌症发病机制的基本见解。 博士首席研究员斯科特奥克斯是医学博士，他已经完成了解剖病理学的住院医师培训，并希望发展一个独立的研究生涯，专注于细胞凋亡的分子途径及其与人类疾病的关系。申办者Stanley J. Korsmeyer博士是细胞凋亡领域的世界领导者，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.