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：
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
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/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

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导致儿童死亡和残疾的主要原因。事实上，脑损伤后的生存质量是危重儿童（包括患有癌症等共病的儿童）最大的不可逆转的未满足需求。婴儿和儿童脑缺氧缺血的最常见原因是心脏骤停。然而，脑缺氧缺血会对许多其他疾病的生活质量产生负面影响，包括创伤性脑损伤、中风、脑出血以及炎症和神经退行性疾病。最常见的结果是令人沮丧的发病率或死亡率，生存率与缺氧缺血性脑病（HIE）的程度直接相关，以及认为护理无效。迫切需要强有力的疗法来预防和/或治疗心脏骤停后以及由许多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，线粒体受损，产生有毒自由基，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；以及强大的炎症介质。所有这些潜在病理机制的核心是活性氧 (ROS) 的超生理产生，这使得线粒体产生的 ROS 成为 HIE 合乎逻辑且具有潜在影响力的治疗靶点。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。需要一种范式转变的方法，例如阻止ROS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缀合的“治疗有效负载”：i)利用线粒体和细菌之间的共同祖先，对线粒体膜具有高亲和力的抗菌剂中使用的化学部分；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，我们很幸运能够合成和开发一系列有前途的基于氮氧自由基的线粒体靶向疗法，与传统的抗氧化剂相比，这些疗法主要充当电子清除剂，从而防止ROS的形成。此外，我们准备在我们的发育中大脑缺氧缺血模型中测试这些强大的线粒体靶向疗法，包括我们的临床相关的儿童窒息心脏骤停模型。这项研究的目的是合成和开发新型线粒体靶向疗法，以有意义地改善患有脑缺氧缺血的婴儿和儿童的神经结果和生活质量。