BAX/BAK control ER-mitochondria apoptotic crosstalk

BAX/BAK 控制 ER-线粒体凋亡串扰

• 批准号: 7227022
• 负责人: Scott A. Oakes
• 金额: $ 11.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227022
• 关键词: Affect; Anatomy; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmunity; BAK1 gene; Calcium; Calcium Signaling; Cell Death; Cells; Cessation of life; Complex; Defect; Development; Doctor of Medicine; Embryo; Endoplasmic Reticulum; Excision; Family member; Fibroblasts; Homeostasis; Immune; Immune system; Lead; Localized; Lymphocyte; Lymphoid; Maintenance; Malignant Neoplasms; Measures; Mitochondria; Molecular; Mus; Mutate; Organelles; Pathogenesis; Pathology; Pathway interactions; Physiological; Play; Principal Investigator; Protein Family; Proteins; Range; Regulation; Research; Research Personnel; Residencies; Resistance; Role; Role playing therapy; Signal Pathway; Signal Transduction; Stimulus; T-Lymphocyte; TCR Activation; Thinking; Training; Work; aged; apoptosis in lymphocytes; base; career; cell suicide; defined contribution; fetal; human disease; in utero; insight; leukemia/lymphoma; member; reconstitution; response; transcription factor; uptake

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.

描述（由申请人提供）：细胞凋亡或程序性细胞死亡是一种生理形式的自杀形式，可严格调节免疫系统的发育和稳态。去除自反应或受损的淋巴细胞的缺陷被认为会导致自身免疫性疾病和白血病/淋巴瘤。因此，了解淋巴细胞凋亡中涉及的信号传导途径仍然是一个重要的挑战。在Bax/Bak（DKO）中，两名促凋亡的Bcl-2家族成员的小鼠在子宫内产生并大部分死亡。 DKO小鼠胚胎成纤维细胞或胎儿衍生的淋巴细胞重构为RAG-1 - / - 小鼠，对响应广泛的死亡刺激，对凋亡具有显着抗性，包括专门针对内质网（ER）的信号。虽然最初通过在线粒体上接受活化的BH3蛋白来起作用，但初步研究强烈表明，Bax/Bak在维持ER Ca2+存储和控制ER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，该提案旨在了解Bax/Bak Control CA2+存储如何以及它在调节线粒体依赖性凋亡中的作用。 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.进一步的工作将定义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理的基本见解。 首席研究员斯科特·奥克斯（Scott Oakes）博士是医学博士，他已经完成了解剖病理学的居住培训，并希望发展独立的研究职业，重点介绍了凋亡的分子途径及其与人类疾病的关系。赞助商Stanley J. Korsmeyer博士是凋亡领域的世界领导者，培训成功的基本研究人员的记录很强。

项目成果

The role of endoplasmic reticulum stress in human pathology.

• DOI: 10.1146/annurev-pathol-012513-104649
• 发表时间: 2015
• 期刊: Annual review of pathology
• 作者: Oakes SA;Papa FR
• 通讯作者: Papa FR

The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress.

• DOI: 10.1038/ncb2395
• 发表时间: 2011-12-18
• 期刊: Nature cell biology
• 影响因子: 21.3

Signaling cell death from the endoplasmic reticulum stress response.

• DOI: 10.1016/j.ceb.2010.11.003
• 发表时间: 2011-04
• 期刊: CURRENT OPINION IN CELL BIOLOGY
• 影响因子: 7.5
• 作者: Shore, Gordon C.;Papa, Feroz R.;Oakes, Scott A.
• 通讯作者: Oakes, Scott A.