Endothelial targeting of antioxidants

 描述（由申请人提供）：血管氧化应激和炎症是许多人类疾病（包括心血管、神经和肺部急性危险重症监护条件）中相互交织的组织损伤传播机制。许多证据表明，在这些条件下，内皮细胞对细胞因子和其他病理因子的反应产生活性氧。抗氧化剂对内皮没有天然亲和力，并且不淬灭内皮细胞内区室中的ROS。我们通过将抗氧化剂如抗氧化酶（SOD和过氧化氢酶）免疫靶向到内皮细胞内体的特定亚型来实现这一目标。我们以前的初步研究结果表明，这种方法在急性肺部炎症的动物模型中提供了显着的保护。此外，协作双靶向的新发现为协同SOD和过氧化氢酶的伴随递送开辟了途径。在这个项目中，利用我们在靶向抗氧化剂方面的丰富经验和PENN肺移植中心提供的独特合作机会，我们将通过追求以下具体目标，朝着将我们的方法转化为医疗实践迈出决定性的一步。在目标1中，我们将通过将靶向抗氧化剂定位于细胞膜小窝与网格蛋白内体来最大化靶向抗氧化剂的精确度和效果。在目标2中，我们将讨论SOD和过氧化氢酶的双重协同靶向的机制和效用。在目标3中，我们将评估铅制剂在动物中的保护作用和不良作用，基于临床可接受的元素设计翻译靶向抗氧化剂，并在人肺中测试其靶向抗氧化剂。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就位。该项目的实施将揭示血管氧化应激和炎症机制的知之甚少的方面，并为涉及这些条件的人类病理提供新的特异性和有效的治疗。

 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.