Bax function in apoptosis

描述(由申请人提供)：这个项目涉及细胞通过被称为“细胞凋亡”的过程死亡，这对正常的生理和发育都是至关重要的。细胞凋亡对各种疾病的起源和治疗也很重要，包括癌症、艾滋病以及免疫系统和中枢神经系统的紊乱。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，也将为开发更好的疾病治疗方法提供基础。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是如何由属于Bcl-2家族的蛋白质控制的。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。外膜的通透性允许有毒蛋白质的释放，从而触发细胞凋亡过程。最终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外线粒体膜，以帮助揭示Bax形成膜孔的基本机制。其他研究将使用核磁共振光谱来检查某些化合物产生的Bax分子结构变化，这些化合物抑制或促进Bax孔的形成。我们还将研究线粒体膜外膜上的Bax与线粒体膜内另一种名为OPA1的蛋白质之间的通讯。我们还想了解这些蛋白质之间的联系如何与一种遗传性疾病--常染色体显性遗传性视神经萎缩有关，这种疾病是由OPA1突变引起的。 与公共健康相关：细胞通常通过一种预置的内部程序死亡，这种程序被称为“细胞凋亡”。细胞凋亡性死亡对于正常的人体发育、塑造组织和防止多余细胞的积累都是重要的。细胞凋亡在正常的成人器官和免疫系统中也很重要，以保持细胞群的正常大小。如果细胞凋亡受到异常控制，细胞可能会不适当地死亡，导致基本细胞群的丧失，或者可能存活并增殖到不健康的水平。细胞凋亡异常可能与癌症、艾滋病、自身免疫性或神经退行性疾病等疾病有关。此外，癌细胞的凋亡性死亡是癌症治疗的重要组成部分。对于所有这些疾病状态，重要的是了解细胞死亡的基本过程，不仅要了解疾病的起源，而且要帮助设计更有效的治疗方法。如果这个项目得到资助，我们希望揭示线粒体--细胞内产生能量的结构--在导致细胞死亡的各种过程中起关键作用的方式。特别是，我们感兴趣的是与致癌蛋白Bcl2相关的蛋白质家族；特别是关于这些蛋白质如何控制每个线粒体周围膜上毛孔的形成。这种毛孔形成允许有毒蛋白质逃逸，导致细胞死亡。其次，我们想了解另一种蛋白质OPA1是如何在线粒体内正常发挥作用来保持细胞的。我们还想了解OPA1的突变是如何在一种名为“常染色体显性遗传性视神经萎缩”的疾病患者身上发生的，从而在以后的生活中导致遗传性视力丧失。

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.