CALPAINS AND CASPASE-3 IN NEURONAL CELL DEATH

钙蛋白酶和 CASPASE-3 在神经细胞死亡中的作用

• 批准号: 6192714
• 负责人: BRIAN R. PIKE
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6192714
• 关键词: apoptosis; brain injury; calpain; cysteine endopeptidases; cytotoxicity; enzyme activity; enzyme inhibitors; glutamates; hippocampus; mechanical stress; spectrin; staurosporine; tissue /cell culture; trauma

DESCRIPTION: (Verbatim from the Applicant's Abstract) Traumatic brain injury (TBI) is a significant health care issue with approximately 500,000 hospital admissions. Although there has been much progress in understanding he pathological mechanisms associated with TBI, knowledge of the complex and varied biochemical, cellular and molecular cascades affecting the traumatized brain are poorly understood. However, recent advances by our laboratory and others have demonstrated important roles for two families of cysteine proteases, calpains and caspases, in mediating necrotic and/or apoptotic cell death after trauma. Recent development of in vitro models of various components of mechanical and biochemical insults relevant to TBE have provided efficient and powerful tools for dissociation of trauma induced stimuli and subsequent cellular responses. The aim of this proposal is to examine the relative contributory roles of calpains and caspase-3 proteases in various in vitro models of necrosis or apoptosis and in models of mechanical cell injury, glutamate excitotoxicity , and oxygen/glucose deprivation in primary septo-hippocampal cell cultures. Importantly, preliminary work has demonstrated that calpains and caspase-3 proteases can be individually or concurrently activated depending on the mode and/or magnitude of the initiating stimulus. In addition, this work demonstrates the use of caspase-3 activation as a sensitive biochemical marker for detection of apoptosis that is independent of classically defined morphological apoptotic alterations It is thought that result of this research will advance an understanding of the varied pathological responses to cellular insult, and will provide a sound foundation for eventual use of therapeutic interventions in numerous disorders of the central nervous system.

产品说明：创伤性脑损伤（TBI）是一个重要的卫生保健问题，大约有500，000人入院。虽然在理解与TBI相关的病理机制方面已经取得了很大进展，但对影响创伤性脑的复杂和多样的生化、细胞和分子级联的知识知之甚少。然而，最近的进展，我们的实验室和其他人已经证明了两个家庭的半胱氨酸蛋白酶，钙蛋白酶和半胱天冬酶，在介导创伤后坏死和/或凋亡细胞死亡的重要作用。最近开发的各种成分的机械和生化损伤相关的TBE的体外模型提供了有效和强大的工具，创伤诱导的刺激和随后的细胞反应的解离。本提案的目的是研究钙蛋白酶和caspase-3蛋白酶在各种体外模型的坏死或凋亡和模型的机械性细胞损伤，谷氨酸兴奋毒性，氧/葡萄糖剥夺在原隔海马细胞培养的相对贡献的作用。重要的是，初步工作已经证明，钙蛋白酶和半胱天冬酶-3蛋白酶可以单独或同时激活取决于模式和/或启动刺激的大小。此外，这项工作证明了半胱天冬酶-3活化作为检测细胞凋亡的敏感生化标志物的用途，该标志物独立于经典定义的形态学细胞凋亡改变。认为这项研究的结果将促进对细胞损伤的各种病理反应的理解，并将为最终在中枢神经系统的许多疾病中使用治疗干预提供良好的基础。