Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain

线粒体靶向氧化还原疗法治疗发育中大脑缺血

基本信息

批准号：
9193104
负责人：
Hülya Bayir
金额：
$ 39.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193104
关键词：
Acute Affinity Anti-Bacterial Agents Antioxidants Apoptosis Apoptotic Bacteria Biological Blood - brain barrier anatomy Brain Brain Hypoxia-Ischemia Brain Injuries Caring Cations Cause of Death Cell Death Cerebral Ischemia Cerebral Ischemia-Hypoxia Cerebral hemisphere hemorrhage Cessation of life Chemicals Child Childhood Clinical Comorbidity Critically ill children Cytoprotection Disease Dose Electrons Female Free Radical Scavengers Free Radicals Generations Glucose Gramicidin Heart Arrest Histologic Human Huntington Disease Hypoxia In Vitro Infant Inflammation Mediators Inflammatory Injury Inner mitochondrial membrane Lead Libraries Malignant Neoplasms Membrane Potentials Mitochondria Modeling Morbidity - disease rate Necrosis Neurodegenerative Disorders Neurological outcome Neurons Outcome Oxidation-Reduction Oxidative Stress Oxygen Pathologic Pathway interactions Positioning Attribute Property Quality of life Rattus Reactive Oxygen Species Regimen Reperfusion Injury Research Shock Site Stroke Testing Therapeutic Translations Traumatic Brain Injury ascorbate base clinically relevant deprivation disability functional outcomes improved improved outcome in vitro Model in vivo male memory acquisition mitochondrial membrane mortality motor function improvement multidisciplinary neonatal hypoxic-ischemic brain injury neuron loss neuronal survival neuroprotection novel object recognition osteogenic postnatal prevent prototype public health relevance response spatial memory success targeted treatment therapeutic target translational impact

项目摘要

DESCRIPTION (provided by applicant): Brain damage after cerebral hypoxia-ischemia is a major contributor to death and disability in children. In fact, quality survival after brain injuryis the greatest irreversible unmet need in critically ill children, including those with co-morbiditie such as cancer. The most common cause of cerebral hypoxia-ischemia in infants and children is as a consequence of cardiac arrest; although, cerebral hypoxia-ischemia negatively impacts quality of life in many other diseases including traumatic brain injury, stroke, intracerebral hemorrhage, and inflammatory and neurodegenerative diseases. Disheartening morbidity or mortality with survivability directly related to the degree of hypoxic-ischemic encephalopathy (HIE)-and perceived futile care, are the most common outcomes. Robust therapies to prevent and/or treat cerebral hypoxia-ischemia after cardiac arrest and as a consequence of a host of other diseases are urgently needed. At the crux of hypoxia-ischemic injury, are mitochondria. After hypoxia-ischemia damaged mitochondria produce toxic free radicals that directly attack vital cellular constituents; are at the convergence of several critical cell death pathways; and ar powerful mediators of inflammation. Central to all of these potentially pathological mechanisms is the supraphysiologic generation of reactive oxygen species (ROS), making mitochondria-generated ROS a logical and potentially impactful therapeutic target for HIE. To date, strategies targeting ROS have focused on free radical scavengers or replacing endogenous antioxidants to quench these highly reactive compounds. Disappointingly, these strategies have not translated into efficacious treatments. A paradigm-shifting approach is needed, e.g. preventing generation of ROS, rather than attempting to quench them. Novel compounds that target mitochondria include "therapeutic payloads" conjugated with: i) chemical moieties utilized in antibacterial agents that have a high affinity for mitochondrial membranes, taking advantage of the shared ancestry between mitochondria and bacteria; or ii) a cationic moiety, taking advantage of electrophoretic properties and mitochondrial membrane potential. As a multidisciplinary team, we are in the fortunate position to synthesize and develop a library of promising nitroxide-based, mitochondria-targeting therapeutics that function primarily as electron scavengers-in contrast to traditional antioxidants, thus preventing formation of ROS. Furthermore, we are uniquely poised to test these powerful mitochondria- targeting therapies in our models of hypoxia-ischemia in the developing brain, including our clinically relevant model of pediatric asphyxial cardiac arrest. The aim of this research is to synthesize and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.

描述（由申请人提供）：脑缺氧 - 缺血后的脑损伤是儿童死亡和残疾的主要因素。实际上，脑损伤后的质量生存是危重儿童中最大的不可逆的未满足需求，包括患有癌症的人。婴儿和儿童的脑缺氧 - 缺血性的最常见原因是心脏骤停的结果。虽然，脑缺氧 - 缺血症会对许多其他疾病的生活质量产生负面影响，包括脑外伤，中风，脑部出血以及炎症性和神经退行性疾病。最常见的结果是与低氧 - 缺血性脑病（HIE）和感知到的徒劳的沮丧的发病率或死亡率直接相关的，这是最常见的结果。心脏骤停后预防和/或治疗脑缺氧 - 缺血症以及由于许多其他疾病而迫切需要的强大疗法。在缺氧 - 缺血性损伤的关键中，是线粒体。缺氧 - 异常损伤后，线粒体会产生直接攻击重要细胞成分的有毒自由基。处于几个关键细胞死亡途径的收敛；和AR强大的炎症介体。所有这些潜在的病理机制的核心是活性氧（ROS）的超构图生成，使线粒体生成的ROS成为HIE的逻辑且潜在影响的治疗靶标。迄今为止，针对ROS的策略集中在自由基清除剂上或取代内源性抗氧化剂以淬灭这些高反应性化合物。令人失望的是，这些策略尚未转化为有效的治疗方法。需要一种范式移动方法，例如防止产生ROS，而不是试图消除它们。靶向线粒体的新型化合物包括：i）在抗菌剂中使用的化学部分对线粒体膜具有很高亲和力，利用线粒体和细菌之间的共同祖先；或II）阳离子部分，利用电泳特性和线粒体膜电位。作为一个多学科团队，我们处于幸运的位置，可以合成和开发有前途的基于硝基氧化的线粒体靶向疗法的库，这些疗法主要是电子清除剂与传统抗氧化剂的对比，从而防止ROS的形成。此外，我们有独特的准备在发育中的大脑中低氧 - 异化模型中测试这些强大的线粒体靶向疗法，包括我们临床相关的儿科窒息心脏心脏骤停模型。这项研究的目的是综合和开发新颖的线粒体靶向治疗，以有意义地改善患有脑缺氧 - 异常患者的婴儿和儿童的神经系统结果和生活质量。