MITOCHONDRIAL CYCLOPHILILN IN CELL DEATH PATHWAYS

描述（改编自研究者摘要）：编程细胞 死亡（PCD或凋亡）是一种进化上保守的机制 对组织和生物体的发育和维持至关重要 多细胞生物体内的稳态。所有的证据都表明 这与生物学上最相关的 在效应期调节PCD过程的蛋白质类 所有PCD过程的共同点是与bcl-2相关的蛋白质家族， 基因产物主要研究者打算测试当前模型 这个蛋白质家族的作用，调用调节 bcl-2家族成员的线粒体通透性转换（PT）， 导致早期线粒体事件的调节， PCD途径。PT被纳摩尔浓度的 免疫抑制肽环孢菌素A（CsA），如PCD在许多 分析系统大量的数据表明唯一已知的目标 CsA在线粒体中的作用是CyP-D， 其酶活性被CsA抑制的亲环素和多种 非免疫抑制类似物。本提案的具体重点 然后是明确地解决有关的基本问题：1） CsA抑制PT的机制; 2）CyP-D对PT的影响 PT在PCD及其他病理过程中的作用。三 提出了目标。目的1是建立CyP-D基因敲除小鼠。第二 目的是描述其表型。最后，校长 研究者将在细胞水平表征小鼠， 确定对线粒体功能的影响。

DESCRIPTION (adapted from investigator's abstract): Programmed cell death (PCD or apoptosis) is an evolutionarily conserved mechanism essential for the development and maintenance of tissue and organismal homeostasis in multicellular organisms. All available evidence is consistent with the idea that one of the most biologically relevant classes of proteins regulating PCD processes at the effector phase common to all PCD processes is a family of proteins related to the bcl-2 gene product. The Principal Investigator intends to test current models of the action of this family of proteins which invoke regulation of the mitochondria permeability transition (PT) by bcl-2 family members, leading to modulation of early mitochondria events which characterize PCD pathways. The PT is inhibited by nanomolar concentrations of the immunosuppressant peptide cyclosporin A (CsA), as is PCD in a number of assay systems. A large body of data indicates that the only known target of CsA action in mitochondria is CyP-D, a mitochondria matrix cyclophilin whose enzymatic activity is inhibited by CsA and a variety of non-immunosuppressive analogs. The specific focus of this proposal is then to unambiguously resolve basic questions related to: 1) the mechanism of PT inhibition by CsA, 2) the influence of CyP-D on the PT and 3) the role of the PT in PCD and other pathological processes. Three aims are proposed. Aim 1 is to generate CyP-D knockout mice. The second aim is to characterize their phenotypes. Finally, the Principal Investigator will characterize the mice at the cellular level to determine the effects on mitochondrial function.