Delayed Tolerance After Hypothermic Preconditioning

描述(摘自申请者摘要)：缺血性损伤是一种常见的 在广泛的外科手术中出现并发症。实施低温治疗 在缺血事件期间和/或在证明对临床有益之后， 其效果可与其他治疗策略相媲美或超过。这 应用描述了一种新的治疗策略，其中短暂的低温 预适应用于诱导延迟形式的缺血耐受， 会持续几天。有证据表明，体温过低 预适应显著减少短暂性脑梗塞 局灶性缺血，这种耐受现象依赖于蛋白质合成 它发生在位于脑实质中的细胞中。拟议中的工作 将表征治疗、细胞和分子特征 通过解决以下具体问题来诱导低温耐受：1) 诱导耐受性的最佳低温条件是什么？2)可以 低温诱导的耐受性补充了 脑缺血内低温？3)哪些细胞类型起作用 低温诱导的耐受性？4)a.哪些候选基因参与调节 宽容？B.哪些细胞类型表达候选基因？C.扮演什么角色 这些基因在缺血性神经保护中起作用吗？这个项目的最终目标是 是开发一种新的治疗策略，其中简单的预适应 在手术前很好地进行治疗可以用来限制随后的 缺血性损伤。一个类似的目标是确定细胞位置和分子 组织耐受性的机制。因为体温过低已经是 在人类手术中安全使用，这一新策略可能会 在临床环境中迅速实施。低温预适应 可以提供一种低风险的方法来改善术后的手术结果 几乎任何形式的侵入性手术，包括高危神经和 心血管手术。此外，由于相对良性的性质， 低温预适应，也将有可能细化搜索 重要的细胞和分子事件与神经耐受有关。这 方法最终将促进以基因为基础的新技术的发展 限制缺血损伤的治疗方法。

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.