Delayed Tolerance After Hypothermic Preconditioning

描述（改编自申请人摘要）：缺血性损伤是常见的 广泛的外科手术并发症。给予低温治疗 在缺血事件期间和/或之后已经证明是临床有益的， 其效果与其他治疗策略相当或超过其他治疗策略。这 该申请描述了一种新的治疗策略，其中短暂的低体温 预处理用于诱导延迟形式的缺血耐受， 持续几天。有证据表明，低体温 预处理显著减少短暂性脑梗死 局灶性缺血，这种耐受现象是蛋白质合成依赖性的 并且它发生在位于脑实质中的细胞中。拟议工作 将描述治疗，细胞和分子特征， 通过解决以下具体问题来解决低血糖诱导的耐受性：1） 诱导耐受的最佳低温条件是什么？2)可以 低血糖诱导的耐受性补充了 局部缺血性低温3)哪些细胞类型有助于 低血糖诱导的耐受性4)a.哪些候选基因介导 宽容？B.哪些细胞类型表达候选基因？C.什么角色 这些基因在缺血性神经保护中发挥作用？这个项目的最终目标 是开发一种新的治疗策略， 在手术前进行治疗，可以用来限制随后的 缺血性损伤一个平行的目标是确定细胞位点和分子 负责组织耐受性的机制。尽管体温过低已经 在人类手术中安全使用，这种新策略似乎可以 在临床环境中迅速实施。低温预处理 可以提供一种低风险的方法来改善手术结果， 几乎任何形式的侵入性手术，包括高风险的神经和 心血管手术此外，由于相对良性的性质， 低温预处理，也将有可能完善搜索 负责神经耐受的显著细胞和分子事件。这 这种方法将最终促进新的基于基因的 限制缺血性损伤的治疗。

DESCRIPTION (Adapted from applicant's abstract): Ischemic injury is a common complication in a wide range of surgical procedures. Hypothermia administered during and/or after an ischemic event has proven to be clinically beneficial, and its effects rival or exceed those of other therapeutic strategies. This application describes a novel therapeutic strategy in which brief hypothermic preconditioning is used to induce a delayed form of ischemic tolerance that persists for a few days. Evidence is presented demonstrating that hypothermic preconditioning substantially reduces cerebral infarction elicited by transient focal ischemia, that this tolerance phenomenon is protein synthesis dependent and that it occurs in cells located in the brain parenchyma. The proposed work will characterize therapeutic, cellular and molecular features of hypothermia-induced tolerance by addressing the following specific issues: 1) What are the optimal hypothermic conditions for inducing tolerance? 2) Can hypothermia-induced tolerance complement the protective effects of intraischemic hypothermia? 3) Which cell types contribute to hypothermia-induced tolerance? 4) a. What are the candidate genes for mediating tolerance? b. What cell types express the candidate genes? c. What role do these genes play in ischemic neuroprotection? The ultimate goal of this project is to develop a new therapeutic strategy wherein a simple preconditioning treatment, administered well before surgery, can be used to limit subsequent ischemic injury. A parallel goal is to identify cellular sites and molecular mechanisms responsible for tissue tolerance. In as much as hypothermia is already used safely during human surgery, it is plausible that this new strategy could be implemented rapidly in the clinical setting. Hypothermic preconditioning could provide a low risk approach for improving surgical outcome after virtually any form of invasive surgery, including high-risk neurological and cardiovascular procedures. Moreover, because of the relatively benign nature of hypothermic preconditioning, it will also be possible to refine the search for salient cellular and molecular events responsible for neural tolerance. This approach will ultimately facilitate the development of novel gene-based therapies for limiting ischemic injury.