Protein Kinase C Isozymes in Stroke-Therapeutic Target?

描述（由申请人提供）：在这个国家每年发生超过50万次中风，造成严重的残疾和死亡。目前只有一种治疗方法，重组组织纤溶酶原激活剂（rt-PA），被批准用于中风。然而，只有大约3%的患者接受它，可能是因为治疗的时间窗口很短（3小时或更短）。因此，非常需要可以单独给予或与血栓溶解剂联合给予的有效的神经保护剂。 此外，在某些临床环境中可能需要预防性神经保护。仅在美国，每年就有600，000名成年人和12，000名儿童接受利用心肺转流术的心脏直视手术，在此期间，大脑经历缺血期。尽管在外科手术和缩短缺血性事件的进步，CNS功能障碍仍然是这些患者发病率和死亡率的主要原因。因为在这些患者中缺血性损伤的确切时间是提前知道的，所以在手术前通过用保护脑免受缺血-再灌注损伤的药剂进行预处理存在显著减少心肌损伤的潜力。 我们的假设是，选择蛋白激酶C（PKC）同工酶发挥重要的（积极和/或消极）的作用，在不同阶段的反应，脑缺血性损伤。 使用同工酶特异性抑制剂和激活肽，我们已经开发，我们计划，确定哪些PKC同工酶激活脑缺血后，什么时候发生，并确定是否抑制或激活这些同工酶可以提供保护缺血再灌注损伤的大脑。 这些研究将证明体内递送PKC调节肽用于治疗CNS缺血再灌注损伤的有效性。如果发现治疗有效且安全，则这些PKC活性的肽调节剂可用于治疗人类中风和脑缺血。

DESCRIPTION (provided by applicant): Over 500,000 strokes occur in this country annually, causing significant disability and death. Only one treatment, recombinant tissue plasminogen activator (rt-PA), is currently approved for stroke. However, just about 3% of the patients receive it, probably because the time-window for therapy is brief (3 hours or less). Therefore, there is a great need for effective neuroprotective agents that could be given alone or in conjunction with thrombolytic agents. Furthermore, prophylactic neuroprotective use may be indicated in certain clinical settings. Each year, in the United States alone, 600,000 adults and 12,000 children undergo open heart operations utilizing cardiopulmonary bypass, during which the brain is subjected to periods of ischemia. Despite advances in surgical procedures and shortening of the ischemic event, CNS dysfunction remains a leading cause of morbidity and mortality in these patients. Because the exact timing of the ischemic insult is known ahead of time in these patients, the potential exists to significantly reduce myocardial damage by pre-treatment with agents that protect the brain from ischemia-reperfusion damage prior to surgery. Our HYPOTHESIS is that select protein kinase C (PKC) isozymes play an important (positive and/or negative) role in the various stages of response of the brain to ischemic insult. Using isozyme-specific inhibitor and activator peptides that we have developed, we plan to; determine which PKC isozymes are activated following cerebral ischemia and when does that occur, and determine whether inhibition or activation of these isozymes can provide protection from ischemic reperfusion damage to the brain. These studies will demonstrate the effectiveness of in vivo delivery of PKC regulating peptides for the treatment of ischemic reperfusion injury of the CNS. Should the treatment be found efficacious and safe, these peptide regulators of PKC activity may be useful for the treatment of stroke and brain ischemia in humans.