The Role of CaMK Cascade in Stroke

CaMK 级联在中风中的作用

• 批准号: 8655184
• 负责人: Jun Li
• 金额: $ 33.17万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655184
• 关键词: Aging; Behavioral; Blood - brain barrier anatomy; Brain; Calcium; Calcium Signaling; Calcium/calmodulin-dependent protein kinase; Cause of Death; Cell Death; Cerebral Ischemia; Clinical Trials; Data; Dominant-Negative Mutation; Functional disorder; Gene Deletion; Gene Expression; Goals; Inflammation; Injury; Investigation; Ischemia; Ischemic Stroke; Lentivirus Vector; Mediator of activation protein; Middle Cerebral Artery Occlusion; Mus; Neuronal Injury; Outcome; Pathology; Pathway interactions; Patients; Phosphotransferases; Play; Protein Isoforms; Protein Kinase; Proteins; Recovery of Function; Relative (related person); Role; Signal Pathway; Signal Transduction; Solutions; Stroke; System; Testing; Transcriptional Activation; Transfection; Viral; aged; aging brain; disability; improved; in vivo; neuroprotection; novel; post stroke; tool

DESCRIPTION (provided by applicant): Calcium signaling plays a critical role in the pathology of cerebral ischemia. However, clinical trials testing treatments which block calcium signaling have failed to improve outcomes in patients with ischemic stroke. One possible explanation is that these agents also inhibited potentially beneficial effects of raised intracellular calcium. Emerging data suggest that calcium may trigger endogenous protective pathways in the ischemic brain. A logical solution is to augment the endogenous protective mechanisms induced by increased calcium, while inhibiting the detrimental effects of excessive calcium. We discovered that CaMKK (calcium/calmodulin-dependent protein kinase kinase), a major kinase in calcium signaling, is implicated in endogenous neuroprotection after stroke. The overall goal of this proposal is to study the functional roles of CaMKK in stroke and uncover the mechanism by which CaMKK signaling activates pro-survival pathways after stroke. CaMKK activates its downstream kinases CaMK I and CaMK IV (together these three kinases are termed the "CaMK cascade"). We will test the hypothesis that CaMK I/IV are important mediators of CaMKK's neuroprotective actions in stroke. Both kinases target multiple critical cell death/survival pathways and our preliminary data definitively show that loss of components of this cellular cascade exacerbate ischemic injury. Finally, our and others' findings have demonstrated that there is a decline in the levels of proteins involved in CaMK signaling in the brain during aging. We will test if activating this cascade in young and aging brain reduces stroke damage and improves post-stroke functional recovery. We will use a combination of pharmacological tools, mice with targeted deletions of these kinases, and viral transfection systems to over-express or in-activate these kinases in vivo. These studies represent the first steps in improving our understanding of the endogenous signaling pathways that are activated by calcium in the ischemic brain.

描述(申请人提供)：钙信号在脑缺血的病理中起关键作用。然而，测试阻断钙信号的治疗方法的临床试验未能改善缺血性中风患者的预后。一种可能的解释是，这些药物还抑制了细胞内钙升高的潜在有益影响。新出现的数据表明，钙可能会在缺血脑中触发内源性保护通路。一个合理的解决方案是加强钙含量增加所诱导的内源性保护机制，同时抑制过量钙的有害影响。我们发现钙/钙调蛋白依赖的蛋白激酶CaMKK(钙/钙调蛋白依赖的蛋白激酶)，是钙信号转导中的一种主要的激酶，与卒中后的内源性神经保护有关。该方案的总体目标是研究CaMKK在卒中中的功能作用，并揭示CaMKK信号激活卒中后支持生存的通路的机制。CaMKK激活其下游的CaMK I和CaMK IV(这三个激酶一起被称为“CaMK级联”)。我们将验证这一假设，即CaMK I/IV是CaMKK在中风中神经保护作用的重要中介。这两种激酶都针对多条关键的细胞死亡/生存途径，我们的初步数据明确地表明，这种细胞级联反应的成分的丢失加剧了缺血性损伤。最后，我们和其他人的发现表明，在衰老过程中，大脑中参与CaMK信号传递的蛋白质水平下降。我们将测试在年轻和老化的大脑中激活这一级联反应是否可以减少中风损伤并促进中风后的功能恢复。我们将结合使用药理学工具、靶向缺失这些激酶的小鼠和病毒转染系统来在体内过度表达或灭活这些激酶。这些研究是提高我们对缺血脑中钙激活的内源性信号通路的理解的第一步。