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。线粒体作为细胞程序性死亡(细胞凋亡)的控制者也起着重要作用。从恶性肿瘤到自身免疫性疾病再到动脉粥样硬化，非调控的细胞凋亡是各种疾病的基础。线粒体在疾病状态中的基本作用似乎与存在于线粒体和细胞质之间的信号通路密切相关。也许最重要的途径包括将细胞色素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，线粒体释放细胞色素c的机制仍然知之甚少。因此，这项为期五年的计划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释放细胞色素c之间的关系。2)探讨bc1-2家族蛋白表达的机制。Bax，促进线粒体细胞色素c的释放。通过对线粒体凋亡途径的研究。这项提议将为线粒体疾病提供新的见解，并将为候选人在线粒体医学研究中的未来奠定基础。这项提案的具体目标将确定线粒体膜孔参与线粒体细胞色素c释放的机制。此外，候选人将发展基本研究技能和对线粒体生物学过程的深入了解，这将使他成为线粒体医学研究领域的独立研究员。这项提议的长期目标是为在与线粒体在疾病中的作用相关的医学研究中发展富有成效的职业生涯奠定基础，线粒体在疾病中的作用是一个迅速增长的研究领域。在这方面，候选人很幸运地与非常成功的科学家建立了导师关系，在一个有利于他作为独立调查员发展的环境中。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Douglas Pfeiffer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，成功的合作倡议的前景是极好的。

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.