Bax function in apoptosis

项目描述（由申请人提供）：本项目涉及细胞通过“凋亡”过程死亡，这对正常生理和发育都至关重要。细胞凋亡对各种疾病的起源和治疗也很重要，包括癌症、艾滋病、免疫系统和中枢神经系统紊乱。对凋亡细胞死亡机制的基本了解将有助于我们理解正常的细胞生理学，并为开发更好的疾病治疗提供基础。在这个项目中，我们感兴趣的是线粒体如何在凋亡细胞死亡中发挥关键作用，以及这种细胞死亡功能如何由属于Bcl-2家族的蛋白质控制。特别是，我们想了解其中一种蛋白质Bax是如何在线粒体外膜上形成孔的。外膜的通透性允许释放触发细胞凋亡过程的有毒蛋白。最终的结果是细胞被主动分解，然后被称为吞噬细胞的其他细胞消耗和破坏。我们的研究将使用我们开发的无细胞系统，使用人工膜或分离的线粒体外膜，来帮助揭示Bax形成膜孔的基本机制。其他研究将使用核磁共振波谱来检查由某些抑制或促进Bax孔形成的化合物产生的Bax分子的结构变化。我们还将研究线粒体外膜上的Bax和线粒体内膜上的另一种叫做Opa1的蛋白质之间的交流。我们还想了解这些蛋白之间的联系如何与一种遗传性疾病有关，即常染色体显性视神经萎缩，这是由Opa1突变引起的。

DESCRIPTION (provided by applicant): This project concerns the death of cells through the process called "apoptosis", which is critical both for normal physiology and development. Apoptosis is also important for the origin and treatment of various diseases, including cancer, AIDS, and disorders of the immune system and the central nervous system. A basic understanding of the apoptotic cell death machinery will help us understand both normal cellular physiology and also provide a foundation for developing better disease therapies. In this project, we are interested in how mitochondria play a key role in apoptotic cell death and how this cell death function is controlled by proteins belonging to the Bcl-2 family. In particular, we want to understand how one of these proteins, Bax, forms pores in the mitochondrial outer membrane. Permeabilization of the outer membrane allows the release of toxic proteins that trigger the apoptotic process. The end result is that cells are actively dismantled and then consumed and destroyed by other cells called phagocytes. Our studies will use cell-free systems we have developed, using either artificial membranes or isolated outer mitochondrial membranes, to help uncover the basic mechanisms through which Bax forms membrane pores. Other studies will use NMR spectroscopy to examine structural changes in the Bax molecule produced by certain compounds that inhibit or promote Bax pore formation. We will also examine the communication that occurs between Bax, at the outer mitochondrial membrane and another protein called Opa1, in the inner mitochondrial membrane. We also want to understand how the linkage between these proteins may relate to a genetic disease, Autosomal Dominant Optic Atrophy, which is caused by mutations in Opa1. PUBLIC HEALTH RELEVANCE: Cells often die by a preset internal program called "apoptosis". Apoptotic cell death is important in both normal human development, in sculpting tissues and preventing the accumulation of excess cells. Apoptosis is also important in normal adult organs and the immune system, to keep cell populations at normal sizes. If apoptotic cell death is abnormally controlled, cells can either die inappropriately, leading to a loss of essential cell populations, or can survive and proliferate to an unhealthy level. Abnormal apoptosis can be involved in such diseases such as cancer, AIDS, and autoimmune or neurodegenerative disorders. Furthermore, apoptotic death of cancer cells is an important component of cancer therapy. For all these disease states, it is important to understand the basic processes involved in cell death, not only to understand disease origins, but also to help devise more effective treatments. If this project is funded, we want to uncover the ways in which mitochondria, energy-producing structures inside cells, are critical for various processes that lead to cell death. In particular, we are interested in a family of proteins related to a pro-cancer protein, Bcl-2; especially with regard to how these proteins control the formation of pores in the membrane surrounding each mitochondrion. This pore formation allows toxic proteins to escape, leading to cell death. Secondly, we want to understand how another protein, Opa1, functions normally within mitochondria to keep cells. We also want to understand how mutations of Opa1 that occur in patients with a disease called "Autosomal Dominant Optic Atrophy" can cause hereditary loss of vision later in life.