Endothelial targeting of antioxidants

 描述(申请人提供)：血管氧化应激和炎症是许多人类疾病中相互交织的组织损伤的传播机制，包括心血管、神经和肺的急性危险重症监护条件。许多证据表明，在这些情况下，内皮细胞对细胞因子和其他病理因素做出反应时产生的活性氧物种。抗氧化剂对内皮没有天然的亲和力，也不能猝灭内皮细胞内的ROS。我们通过免疫靶向抗氧化剂，如抗氧化酶(超氧化物歧化酶和过氧化氢酶)进入特定亚型的内皮内体来实现这一目标。我们先前和初步研究的结果表明，这种方法在急性肺部炎症的动物模型中提供了显著的保护作用。此外，协作双靶向的新发现为协同传递超氧化物歧化酶和过氧化氢酶开辟了新的途径。在这个项目中，我们将利用我们在靶向抗氧化剂方面的丰富经验和宾夕法尼亚大学肺移植中心提供的独特合作机会，通过追求以下具体目标，为我们的医疗实践方法的转化迈出决定性的一步。在目标1中，我们将最大限度地提高目标抗氧化剂的精确度和效果，方法是将它们定位于空泡和笼状蛋白内体。在目标2中，我们将讨论超氧化物歧化酶和过氧化氢酶双重协同靶向的机制和用途。在目标3中，我们将评估铅制剂对动物的保护和不良影响，根据临床可接受的元素设计翻译靶向抗氧化剂，并测试它们在人类肺部的靶向抗氧化剂。研究的所有组成部分，包括独特的试剂、模型和方法，都在我们的合作团队中到位。该项目的实施将揭示血管氧化应激和炎症机制知之甚少的方面，并为涉及这些疾病的人类病理提供新的特异和有效的治疗方法。

 DESCRIPTION (provided by applicant): Vascular oxidative stress and inflammation are intertwined mutually propagating mechanisms of tissue injury in many human maladies including cardiovascular, neurological and pulmonary acute dangerous critical care conditions. Much evidence implicate reactive oxygen species produced by endothelial cells in these conditions in response to cytokines and other pathological agents. Antioxidants have no natural affinity to endothelium and do not quench ROS in endothelial intracellular compartments. We achieve this goal by immunotargeting antioxidants such as antioxidant enzymes (SOD and catalase) into specific sub-types of endothelial endosomes. Results of our previous and pilot studies show that this approach affords remarkable protection in animal models of acute pulmonary inflammation. Further, new findings of collaborative dual targeting open avenues for concomitant delivery of synergizing SOD and catalase. In this project that capitalizes on the wealth of our experience in targeted antioxidants and on unique collaborative opportunities offered by PENN Lung Transplant Center, we will make the decisive steps towards translation of our approach to medical practice via pursuing the following Specific Aims. In Aim 1 we will maximize precision and effect of targeted antioxidants by addressing them to caveolar vs clathrin endosomes. In Aim 2 we will address the mechanism and utility of dual collaborative targeting of SOD and catalase. In Aim 3 we will appraise protective and adverse effects of lead formulations in animals, devise translational targeted antioxidants based on clinically acceptable elements and test their targeting antioxidants in human lungs. All components of the study including unique reagents, models and methods are in place in our collaborative team. Implementation of this project will shed light on poorly understood aspects of mechanisms of vascular oxidative stress and inflammation and provide new specific and potent treatment for human pathologies involving these conditions.