Effect of Glutamine on HSP-70 Expression in ICU patients

描述(由申请人提供)： 众所周知，热休克蛋白-70(HSP-70)的表达增强可以保护细胞和组织免受损伤。此外，HSP-70的表达可以提高危重疾病实验模型的存活率。然而，这些发现还没有临床应用，因为已知的HSP-70增强剂对人类给药是不安全的。因此，这一非常强大的工具，可能会显著改善危重患者的预后，但尚未在临床上应用。本实验室研究表明，谷氨酰胺(Gln)可促进应激动物组织中HSP-70的表达。这种表达与危重疾病实验模型后存活率的提高有关。在一项针对危重病患者的小型初始试验中，我们证明了谷氨酰胺可以在治疗一周后提高血清HSP-70水平。谷氨酰胺对组织HSP-70表达的影响及其改善患者预后的潜力尚不清楚。我们提出了三个具体目标。第一项研究考察了谷氨酰胺对热应激后健康志愿者血清和细胞HSP-70表达的影响。这项试验将评估是否可以在应激事件(如手术)之前预先诱导HSP-70以改善结果。第二个具体目标是评估Gln对危重疾病患者血清和细胞HSP-70表达的影响。第三个具体目标将检查潜在增强的HSP-70表达对临床结果的影响。我们相信这项研究将证明Gln是第一个在临床上可行的HSP-70表达增强子。这种药物在降低外科和危重疾病的发病率/死亡率方面的潜力是巨大的。

DESCRIPTION (provided by applicant): It is well known that enhanced heat shock protein-70 (HSP-70) expression can protect cells and tissues from injury. Further, HSP-70 expression can improve survival in experimental models of critical illness. However, clinical application of these findings has not occurred, as known enhancers of HSP-70 are not safe for human administration. Thus, this very powerful tool, that could possibly significantly improve outcome in critically ill patients, has yet to be clinically applied. Our laboratory has shown that the amino acid glutamine (GLN) can enhance HSP-70 expression in tissues of stressed animals. This expression is correlated with improved survival following experimental models of critical illness. In a small initial trial of critically ill patients we demonstrated GLN could enhance serum HSP-70 levels after one-week of therapy. The effect of GLN on tissue HSP-70 expression and its potential to improve outcomes in patients is unknown. We propose three Specific Aims. The first examines GLN's effect on serum and cellular HSP-70 expression in healthy volunteers following a heat stress. This trial will assess if HSP-70 can be pre-induced to improve outcomes prior to a stressful event, such as surgery. The second Specific Aim will be to assess GLN's effect on serum and cellular HSP-70 expression in critical illness. The third Specific Aim will examine the effect of potentially enhanced HSP-70 expression on clinical outcomes. We believe this study will demonstrate that GLN is the first clinically viable enhancer of HSP-70 expression. The potential for such an agent to reduce morbidity/mortality in surgical and critical illness is significant.