Non-apoptotic caspase activity in neurons

神经元中的非凋亡 caspase 活性

• 批准号: 9093400
• 负责人: J. Marie Hardwick
• 金额: $ 23.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093400
• 关键词: Address; Animals; Apoptosis; Apoptotic; Aspartic Acid; Behavior; Biological Neural Networks; Biosensor; Brain; Caspase; Cell Count; Cell Death; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cellular Stress; Cessation of life; Cleaved cell; Color; Development; Drosophila genus; Equilibrium; Exhibits; Family; Functional disorder; Goals; Injury; Label; Life; Mammals; Mediating; Nerve Degeneration; Neurons; Occupations; Odors; Olfactory Pathways; Pathway interactions; Peptide Hydrolases; Physiological; Presynaptic Terminals; Process; Proteins; Reporting; Role; Stimulus; Synapses; Time; Tissues; behavioral response; cell killing; cell type; experience; fly; in vivo; insight; novel; public health relevance; tool

 DESCRIPTION (provided by applicant): Non-apoptotic caspase activity in neurons Caspases are a family of conserved cysteine proteases that orchestrate apoptotic and pyroptotic cell death. Caspase activity is robustly induced shortly before cell death, and caspase-deficient animals have excess cell numbers. Therefore, activation of caspases is often assumed to represent a commitment point towards cell death. However, mounting evidence indicates that caspases also have non-apoptotic roles in healthy cells and tissues. Mammalian and Drosophila neurons have been reported to use caspases for pruning axonal and dendritic process, which is essential for functional neural networks, potentially by similar mechanisms as apoptosis except spatially restricted. However, fly and mammalian caspases have been implicated in a range of other cellular processes, including cell proliferation and differentiation. Caspase activation has been detected in growing axon terminals, and without evidence of cell death. However, the key unanswered questions remain, including what types of neurons display caspase activity and when. Furthermore, very little is known about the non- apoptotic functions of caspase activity in healthy neurons. A number of different caspase biosensors have been developed to detect caspase activation in neurons and other cell types, however available caspase biosensors are not sufficiently sensitive or sustained to address these questions. Therefore, we developed a new dual color caspase biosensor for Drosophila to detect and study non-apoptotic caspase activity in neurons. We propose to determine which neurons exhibit non-apoptotic caspase, and to establish a role for caspases in normal neuronal function. These studies are needed to gain new insights into the mechanisms that connect the normal versus death functions of caspases, as dysregulation of this balance could contribute importantly to neurodegeneration.

 描述（由申请人提供）：神经元中的非凋亡半胱天冬酶活性半胱天冬酶是保守的半胱氨酸蛋白酶家族，其协调凋亡和焦亡细胞死亡。 Caspase 活性在细胞死亡前不久被强烈诱导，并且 Caspase 缺陷的动物细胞数量过多。因此，半胱天冬酶的激活通常被认为代表细胞死亡的承诺点。然而，越来越多的证据表明半胱天冬酶在健康细胞和组织中也具有非凋亡作用。据报道，哺乳动物和果蝇神经元使用半胱天冬酶来修剪轴突和树突过程，这对于功能性神经网络至关重要，其机制可能与细胞凋亡类似，但空间限制除外。然而，果蝇和哺乳动物半胱天冬酶与一系列其他细胞过程有关，包括细胞增殖和分化。在生长的轴突末梢中检测到半胱天冬酶激活，并且没有细胞死亡的证据。然而，关键的悬而未决的问题仍然存在，包括什么类型的神经元表现出半胱天冬酶活性以及何时表现出半胱天冬酶活性。此外，对于健康神经元中半胱天冬酶活性的非凋亡功能知之甚少。已经开发了许多不同的半胱天冬酶生物传感器来检测神经元和其他细胞类型中的半胱天冬酶激活，但是可用的半胱天冬酶生物传感器不够灵敏或持续性不足以解决这些问题。因此，我们为果蝇开发了一种新型双色 caspase 生物传感器，用于检测和研究神经元中的非凋亡 caspase 活性。我们建议确定哪些神经元表现出非凋亡 caspase，并确定 caspase 在正常神经元功能中的作用。需要这些研究来深入了解半胱天冬酶正常功能与死亡功能之间的联系机制，因为这种平衡的失调可能对神经退行性疾病产生重要影响。