The Role of CaMK Cascade in Stroke

CaMK 级联在中风中的作用

• 批准号: 8399915
• 负责人: Jun Li
• 金额: $ 33.52万
• 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/8399915
• 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. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death in the U.S., and the most common cause of disability. We have recently found that CaMKK signaling is an important contributor to the protection induced by the brain during injury. In this application, we will purse a focused investigation on the functional role of this signaling pathway in stroke in an attempt to develop novel treatmentsfor stroke.

描述（由申请人提供）：钙信号传导在脑缺血的病理学中起关键作用。然而，测试阻断钙信号传导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，这些药物也抑制了细胞内钙升高的潜在有益作用。新出现的数据表明，钙可以触发缺血性脑中的内源性保护途径。一个合理的解决方案是增加由钙增加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，CaMKK（钙/钙调蛋白依赖性蛋白激酶激酶），钙信号传导中的主要激酶，涉及中风后的内源性神经保护。该提案的总体目标是研究CaMKK在卒中中的功能作用，并揭示CaMKK信号转导激活卒中后促生存通路的机制。CaMKK激活其下游激酶CaMK I和CaMK IV（这三种激酶一起被称为“CaMK级联”）。我们将测试的假设，CaMK I/IV是重要的介质CaMKK的神经保护作用，在中风。这两种激酶都靶向多个关键的细胞死亡/存活途径，我们的初步数据明确表明，这种细胞级联反应的组分的丢失会加剧缺血性损伤。最后，我们和其他人的研究结果表明，在衰老过程中，大脑中参与CaMK信号传导的蛋白质水平下降。我们将测试在年轻和衰老的大脑中激活这种级联反应是否会减少中风损伤并改善中风后的功能恢复。我们将使用药理学工具、靶向缺失这些激酶的小鼠和病毒转染系统的组合来在体内过表达或失活这些激酶。这些研究代表了改善我们对缺血性脑中钙激活的内源性信号通路的理解的第一步。 公共卫生相关性：中风是美国第三大死亡原因，也是导致残疾的最常见原因我们最近发现，CaMKK信号是一个重要的贡献者，在脑损伤诱导的保护。在本申请中，我们将集中研究该信号通路在中风中的功能作用，试图 develop发展novel新treatments治疗for stroke中风.