Regulation and role of dynamin-related GTPases in C. elegans apoptosis

动力相关 GTP 酶在秀丽隐杆线虫细胞凋亡中的调节和作用

• 批准号: 7689866
• 负责人: BARBARA CONRADT
• 金额: $ 28.78万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689866
• 关键词: Address; Affect; Apoptosis; Apoptotic; Autoimmune Diseases; Binding; Biochemical; Biochemical Genetics; Biological; Biology; Caenorhabditis elegans; Cell Death; Cells; Development; Disease; Dynamin; Family member; Genetic; Genetic Screening; Goals; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Knowledge; Malignant Neoplasms; Mammals; Mediating; Mitochondria; Modeling; Molecular Genetics; Neurodegenerative Disorders; Organelles; Organism; Phenotype; Post-Translational Protein Processing; Process; Property; Proteins; Regulation; Relative (related person); Role; Shapes; Site; System; Testing; Tubular formation; Work; base; cytochrome c; genetic analysis; improved; in vitro activity; in vivo; mitochondrial membrane; overexpression; release factor; research study; tool

DESCRIPTION (provided by applicant): Key questions about apoptosis remain to be answered. For example, neither the role nor the regulation of dynamin-related GTPases is fully understood. Experiments are proposed that address these questions in the worm Caenorhabditis elegans, an organism that has proven to be a powerful tool for apoptosis studies. Dynamin-related GTPases required for mitochondrial membrane dynamics have recently been implicated in apoptosis in worms and mammals. For example, the C. elegans dynamin-related protein DRP-1 is at least partially required for apoptosis and can be sufficient for apoptosis when ectopically expressed. How DRP-1 contributes to apoptosis is currently unclear. One model that has been proposed is that DRP-1 induces mitochondrial division thereby causing mitochondrial fragmentation; however this model remains to be tested. Furthermore, members of the family of Bcl-2-like proteins have been implicated in the regulation of dynamin-related GTPases in apoptotic cells. For example, in C. elegans, the Bcl-2 family members EGL-1 and CED-9 are required for DRP-1-mediated mitochondrial fragmentation in apoptotic cells. How EGL-1 and CED-9 regulate the activity of DRP-1 during apoptosis is currently unknown. However, our preliminary results suggest that CED-9 and DRP- 1 might physically interact in apoptotic cells. The goal of the proposed studies is to investigate the mechanisms through which DRP-1 contributes to apoptosis and to determine the role of the Bcl-2 family members EGL-1 and CED- 9 in the regulation of DRP-1 in apoptotic cells. To that end, we will use biochemical, cell- biological and genetic approaches and perform studies in C. elegans and in vitro. Deregulated apoptosis contributes to the development and manifestation of a number of diseases such as cancer, autoimmune diseases and neurodegenerative diseases. Key questions about the biology of apoptosis remain to be answered and the studies proposed address some of these questions. Therefore, results from the proposed studies will improve our knowledge of apoptosis and hence our ability to understand and treat various human disorders.

描述（由申请人提供）：关于细胞凋亡的关键问题仍有待回答。例如，与动力相关的 GTP 酶的作用和调节尚不完全清楚。提出了在秀丽隐杆线虫中解决这些问题的实验，这种生物体已被证明是细胞凋亡研究的有力工具。线粒体膜动力学所需的动力相关 GTP 酶最近被发现与蠕虫和哺乳动物的细胞凋亡有关。例如，线虫动力相关蛋白DRP-1至少部分是细胞凋亡所必需的，并且当异位表达时足以用于细胞凋亡。目前尚不清楚 DRP-1 如何促进细胞凋亡。已提出的一种模型是 DRP-1 诱导线粒体分裂，从而导致线粒体断裂。然而这个模型还有待测试。此外，Bcl-2 样蛋白家族的成员参与了凋亡细胞中动力相关 GTP 酶的调节。例如，在线虫中，凋亡细胞中 DRP-1 介导的线粒体断裂需要 Bcl-2 家族成员 EGL-1 和 CED-9。目前尚不清楚 EGL-1 和 CED-9 在细胞凋亡过程中如何调节 DRP-1 的活性。然而，我们的初步结果表明，CED-9 和 DRP-1 可能在凋亡细胞中发生物理相互作用。拟议研究的目的是研究 DRP-1 促进细胞凋亡的机制，并确定 Bcl-2 家族成员 EGL-1 和 CED-9 在凋亡细胞中 DRP-1 调节中的作用。为此，我们将使用生物化学、细胞生物学和遗传学方法，并对秀丽隐杆线虫和体外进行研究。 细胞凋亡失调导致许多疾病的发展和表现，例如癌症、自身免疫性疾病和神经退行性疾病。有关细胞凋亡生物学的关键问题仍有待解答，所提出的研究解决了其中一些问题。因此，拟议研究的结果将提高我们对细胞凋亡的认识，从而提高我们理解和治疗各种人类疾病的能力。