The Role of Cdk5 in Stroke

Cdk5 在中风中的作用

• 批准号: 8304737
• 负责人: James A Bibb
• 金额: $ 34.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304737
• 关键词: Ablation; Adult; Affect; Behavioral; Binding; Biochemical; Blood Clot; Blood coagulation; CDK5 gene; Calpain; Cause of Death; Cells; Cessation of life; Clinical; Clinical Trials; Complex; Coupled; Cytolysis; Data; Functional disorder; Generations; Genetic; Glutamates; Histopathology; Holoenzymes; In Vitro; Infarction; Injury; Ischemic Penumbra; Ischemic Stroke; Knowledge; Lead; Link; Mediating; Membrane; Middle Cerebral Artery Occlusion; Minority; Modeling; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nervous System Physiology; Nervous System Trauma; Neurons; Neuroprotective Agents; Outcome; Patients; Pattern; Peptide Hydrolases; Peptides; Phosphotransferases; Physiological; Protein Kinase; Recovery; Role; Severities; Signal Transduction; Specificity; Stroke; Substrate Specificity; Testing; Time; Translating; Viral; alternative treatment; artery occlusion; brain tissue; cofactor; defined contribution; disability; excitotoxicity; functional disability; improved; insight; mortality; neuroprotection; neurotoxicity; novel; novel strategies; prevent; protein protein interaction; receptor function; response; therapy development; translational study

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability in the U.S. and the third leading cause of mortality world-wide. The most common form, ischemic stoke, is caused by blood clots occluding arterial supply, resulting in permanent neurological damage or death. For a minority of patients, blood clots can be removed or lysed to prevent or limit stroke injury. However, neuroprotectants that improve survival and recovery are not available. Following arterial occlusion, neuronal death spreads outward from the initial infarct as neurons depolarize causing massive glutamate release and hyperactivation of NMDA receptors (NMDAR). As a result, excitotoxic Ca2+ flows into cells where it activates the protease calpain. This excitotoxic cascade is a major component of stroke pathophysiology. However, efforts to block the cascade with NMDAR antagonists have not proven effective in clinical trials due to unwanted effects. We discovered that the protein kinase Cdk5 physically links calpain to the NR2B subunit of NMDARs. Cdk5 is also bound to its activator p35. Through this NR2B-calpain- Cdk5/p35 signaling complex, excitotoxic activation of NMDARs causes calpain to convert p35 to p25. Cdk5 associated with p25 causes neuronal death and has been suggested to mediate to ischemic injury. However little is yet known of how Cdk5 or p35/p25 contributes to stroke pathophysiology or how it may be effectively targeted to improve outcome. Here we propose to characterize the dysregulation of Cdk5 following middle cerebral artery occlusion (MCAO) and determine the neuroprotective effects of loss of Cdk5 or p35 in mice. As a novel strategy to achieve neuroprotection we will target the NR2B-calpain-Cdk5/p35 cascade by identifying functional protein-protein interaction motifs and developing small interfering peptides (SIPs) that prevent calpain-Cdk5 and NR2B-Cdk5 interactions. These SIPs will be optimized as molecules that potently and specifically dissociate the NR2B-calpain-Cdk5/p35 and prevent Cdk5/p25 generation by NMDAR hyperactivation without otherwise affecting the functions of the receptors, calpain, or Cdk5. We will then assess their ability to neuroprotect and improve behavioral and histological outcome in mice subjected to MCAO. These translational studies will advance our knowledge of the mechanisms that mediate stroke injury and derive novel neuroprotectants that will potentially lead to the development of therapies that improving recovery and reduce stroke-related disability. PUBLIC HEALTH RELEVANCE: While stroke is a leading cause of morbidity and mortality, treatments that improve recovery are extremely limited. We will characterize the contribution of the protein kinase Cdk5 and its activating cofactor p35 to stroke injury and develop novel neuroprotectants that disrupt the excitotoxic cascade and prevent Cdk5 from contributing to neuronal death without adversely affecting essential NMDA receptor function. Thus we will provide mechanistic insight to a critical component of stroke injury and derive novel neuroprotectants that may be translated into therapies that limit stroke injury and facilitate recovery.

描述（由申请人提供）：中风是美国成人残疾的主要原因，也是全球第三大死亡原因。最常见的形式是缺血性中风，是由血凝块阻塞动脉供应引起的，导致永久性神经损伤或死亡。对于少数患者，可以清除或溶解血凝块以预防或限制中风损伤。然而，改善生存和恢复的神经保护剂是不可用的。动脉闭塞后，神经元死亡从最初的梗死向外扩散