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

• 批准号: 8733232
• 负责人: Hülya Bayir
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8733232
• 关键词: Affinity; Anti-Bacterial Agents; Antioxidants; Apoptosis; Apoptotic; Bacteria; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; 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; 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; Pathway interactions; Positioning Attribute; Property; Quality of life; Rattus; Reactive Oxygen Species; Regimen; Reperfusion Injury; Research; Shock; Site; Stroke; Testing; Therapeutic; Translating; Translations; Traumatic Brain Injury; ascorbate; base; clinically relevant; deprivation; disability; functional outcomes; improved; in vitro Model; in vivo; male; memory acquisition; mitochondrial membrane; mortality; motor function improvement; multidisciplinary; neonatal hypoxic-ischemic brain injury; neuronal survival; neuroprotection; novel; object recognition; osteogenic; postnatal; prevent; prototype; public health relevance; response; success; therapeutic target

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（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原因。事实上，脑损伤后的高质量生存是危重儿童（包括患有癌症等合并症的儿童）最大的不可逆转的未满足需求。婴儿和儿童脑缺氧缺血最常见的原因是心脏骤停；然而，脑缺氧缺血对许多其他疾病的生活质量有负面影响，包括创伤性脑损伤、中风、脑出血、炎症和神经退行性疾病。令人沮丧的发病率或死亡率与缺氧缺血性脑病（HIE）的程度直接相关，并且认为治疗无效，是最常见的结果。迫切需要强有力的治疗方法来预防和/或治疗心脏骤停后和其他疾病引起的脑缺氧缺血。缺氧缺血性损伤的关键是线粒体。缺氧缺血后，受损的线粒体产生有毒的自由基，直接攻击重要的细胞成分；处于几个关键细胞死亡途径的交汇处；也是炎症的强力介质。所有这些潜在病理机制的核心是活性氧（ROS）的超生理生成，这使得线粒体产生的ROS成为HIE合乎逻辑且潜在有效的治疗靶点。迄今为止，针对ROS的策略主要集中在自由基清除剂或替代内源性抗氧化剂来淬灭这些高活性化合物。令人失望的是，这些策略并没有转化为有效的治疗方法。需要一种范式转换的方法，例如，防止活性氧的产生，而不是试图消灭它们。靶向线粒体的新型化合物包括与以下物质偶联的“治疗有效载荷”：1)抗菌药物中使用的化学成分，对线粒体膜具有高亲和力，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，我们有幸合成和开发了一个有前途的基于氮氧化物的线粒体靶向治疗药物库，与传统的抗氧化剂相比，这些治疗药物主要作为电子清道夫，从而防止ROS的形成。此外，我们在发育中的大脑缺氧缺血模型中测试这些强大的线粒体靶向疗法，包括我们的儿科窒息性心脏骤停的临床相关模型。本研究的目的是合成和开发新的线粒体靶向治疗方法，以有意义地改善脑缺氧缺血婴儿和儿童的神经预后和生活质量。