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.
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.
|Yousuf, Mohammad A; Tan, Chunfeng; Torres-Altoro, Melissa I et al. (2016) Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury. J Neurochem 138:317-27|
|Pozo, Karine; Bibb, James A (2016) The Emerging Role of Cdk5 in Cancer. Trends Cancer 2:606-618|
|Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel et al. (2016) Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum. Sci Rep 6:29812|
|Fan, Gaofeng; Aleem, Saadat; Yang, Ming et al. (2015) Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase. J Biol Chem 290:15934-47|
|Tassin, Tara C; Benavides, David R; Plattner, Florian et al. (2015) Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. J Biol Chem 290:16319-29|
|Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100|
|Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93|
|Mettlach, Gabriel; Polo-Parada, Luis; Peca, Lauren et al. (2014) Enhancement of neuromuscular dynamics and strength behavior using extremely low magnitude mechanical signals in mice. J Biomech 47:162-7|
|Kaikkonen, Leena; Magga, Johanna; Ronkainen, Veli-Pekka et al. (2014) p38? regulates SERCA2a function. J Mol Cell Cardiol 67:86-93|
|Plattner, Florian; Hernández, Adan; Kistler, Tara M et al. (2014) Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 81:1070-1083|
Showing the most recent 10 out of 20 publications