MITOCHONDRIAL CYTOCHROME C RELEASE VIA MEMBRANE PORES

除了它们在细胞能量代谢中的众所周知的作用之外。线粒体还作为程序性细胞死亡（凋亡）的控制器发挥重要作用。 不受调节的细胞凋亡是从恶性肿瘤到自身免疫性疾病和动脉粥样硬化的疾病的基础。线粒体在疾病状态中的基本作用似乎与线粒体和细胞质之间存在的信号传导途径密切相关。也许最重要的途径涉及细胞色素c从线粒体释放到细胞质中，这是细胞凋亡的关键信号。 然而，负责从线粒体释放细胞色素c的机制仍然知之甚少。因此，本五年提案确定了两个具体目标：1）确定线粒体肿胀与分离线粒体制剂中细胞色素c释放之间的关系。 2)为了确定BCl-2家族蛋白。BAX促进细胞色素c从线粒体的释放。通过研究线粒体凋亡途径。这一建议将为线粒体疾病提供新的见解，并将确立候选人在线粒体医学研究方面的未来。本提案的具体目标将定义线粒体膜孔参与线粒体释放细胞色素c的机制。此外，候选人将发展基本的研究技能和深入了解线粒体生物学过程，这将使他成为线粒体医学研究领域的独立研究者。该提案的长期目标是为与线粒体在疾病中的作用相关的医学研究的生产性职业生涯奠定基础，这是一个快速增长的调查领域。 在这方面，候选人很幸运，在一个有利于他发展为独立调查员的环境中，与非常成功的科学家建立了导师关系。该提案将Mark Wewers博士的肺部临床研究专业知识与该项目的发起人道格拉斯法伊弗博士的基础科学专业知识相结合。这些顾问正在积极研究线粒体在疾病发病机制中的作用。因此，作为未来成功的关键决定因素，成功的合作举措前景非常好。

In addition to their well-known role in cellular energy metabolism. mitochondria also serve an important role as controllers of programmed cell death (apoptosis). Unregulated apoptosis is the basis for diseases ranging from malignancy to autoimmune diseases and atherosclerosis. The fundamental role of mitochondria in disease states appears to be intimately linked to signaling pathways that exist between mitochondria and the cytoplasm of the cell. Perhaps the most important pathway involves the release of cytochrome c from mitochondria into the cytoplasm, a critical signal for cell apoptosis. However, the mechanisms responsible for the release of cytochrome c from mitochondria remain poorly understood. Therefore, two Specific Aims have been identified for this five-year proposal: 1) To define the relationship between mitochondrial swelling and the release of cytochrome c from isolated mitochondria preparations. 2) To determine the mechanism through which the BCl-2 family protein. BAX, facilitates the release of cytochrome c from mitochondria. Through investigations of mitochondrial apoptotic pathways. this proposal will provide new insights into mitochondrial diseases and will establish the candidate's future in mitochondrial medical research. The Specific Aims of this proposal will define the mechanisms through which mitochondrial membrane pores participate in the release of cytochrome c from mitochondria. In addition, the candidate will develop basic research skills and in-depth understanding of mitochondrial biological processes that will establish him as an independent investigator in the field of mitochondrial medical research. The long-term goal of this proposal is to develop the foundation for a productive career in medical research related to the role of mitochondria in disease, a rapidly growing area of investigation. In this regard, the candidate is fortunate to have established mentorship with highly successful scientists in an environment conducive to his development as an independent investigator. This proposal integrates the pulmonary clinical research expertise of Dr. Mark Wewers with the basic science expertise of Dr. Douglas Pfeiffer, the sponsors of this project. These advisors are actively investigating the role mitochondria in the pathogenesis of disease. Thus, the prospects for successful collaborative initiatives, a critical determinant of future success, are excellent.