Non-apoptotic cell death in fetal brain injury

胎儿脑损伤中的非凋亡细胞死亡

• 批准号: 9512303
• 负责人: SIDHARTHA TAN
• 金额: $ 47.27万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9512303
• 关键词: Abruptio Placentae; Acute; Address; Adult; Affect; Animal Model; Antioxidants; Apoptosis; Asphyxia Neonatorum; Biochemical; Biological Assay; Birth; Birth trauma; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Cause of Death; Cell Death; Cell Differentiation process; Cerebral Palsy; Chemicals; Child; Clinical; Complex; Control Groups; Cord prolapse; Critical Pathways; Cysteine; Data; Development; Discipline of obstetrics; Disease; Early identification; Electron Microscopy; Electrons; Employee Strikes; Etiology; Event; Fetal Distress; Fetus; Flow Cytometry; Free Radicals; Frequencies; Funding; Future; Glutamates; High Pressure Liquid Chromatography; Hospitals; Human; Hypoxia; Injury; Institution; Iron; Iron Chelating Agents; Laboratories; Lead; Life; Magnetic Resonance Imaging; Mediating; Modeling; Motor Pathways; Mus; Muscle Hypertonia; Necrosis; Newborn Infant; Nitric Oxide; Nitric Oxide Synthase Type I; Oncogenic; Oryctolagus cuniculus; Outcome; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Parents; Parkinson Disease; Pathogenesis; Pathway interactions; Patient Care; Patients; Pattern; Perinatal; Periventricular Leukomalacia; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Placental Insufficiency; Population Study; Pregnancy; Premature Infant; Prevention; Productivity; Publications; Quadriplegia; RIPK1 gene; Reperfusion Therapy; Reporting; Research; Resources; Siblings; Societies; Spastic; Spectrum Analysis; Sulfhydryl Compounds; Superoxides; Surrogate Markers; Suspensions; Techniques; Testing; United States National Institutes of Health; Uterine Rupture; adduct; antenatal; antiporter; base; brain cell; burden of illness; cell injury; cell type; clinical application; clinically relevant; cost; drug development; effective therapy; erastin; fetal; fetal brain injury; human disease; indexing; inhibitor/antagonist; innovation; insight; magnetic resonance imaging biomarker; member; motor deficit; neonatal hypoxic-ischemic brain injury; nervous system disorder; novel therapeutics; postnatal; prenatal; prevent; small molecule; social; spasticity; specific biomarkers; uptake

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a devastating disease usually originating from hypoxia-ischemia (H-I) before birth. It has one of the very highest indices of burden of disease because of the life-long consequences to the patient, the care-takers, and social institutions. The costs to society are huge, to the tune of $11.5 billion, not counting the loss of potential productive members of society. Prevention of a single CP patient would save almost $1.2 million, not factoring loss in productivity of the young parents of CP children. The number of affected CP patients, 800,000 in USA, and burden of disease is higher than many adult neurological diseases affecting the twilight years. Yet, there is a paucity of effective therapies for CP. The lack of progress in CP has been probably because of a lack of sufficient allocated resources, lack of a clinically relevant animal model and a lack of a systematic approach to tackle the problem. The latter two are addressed in this proposal. We will use the rabbit model of CP that develops after acute placental insufficiency at preterm gestation, based on the human disease of abruptio placentae. This H-I model is the first to reliably lead to CP, allowing us to rigorously test not only mechanistic pathways but possible therapies for CP for which there is none currently available. We have identified new novel drugs aimed at inhibiting neuronal nitric oxide synthase (nNOS) and shown that these drugs prevent CP in the rabbit when given antenatally. We have also shown that antenatal antioxidants also similarly prevent CP. With the development of a surrogate marker of MRI, we can predict which fetuses will develop postnatal motor deficits. With H-I, cell death occurs in many forms, including two forms that specifically involve oxidants, called necroptosis and ferroptosis. The main question asked in this proposal is whether the two forms of cell death triggered by oxidants, causes the development of motor deficits. The first Aim will determine which forms of cell death are critically associated specifically with motor deficits. The second Aim will determine if oxidants trigger the critical forms of cell death that lead to motor deficits. The underlying biochemical mechanisms will be studied utilizing the identification of fetuses destined to get postnatal hypertonia and studying entire brain, brain regions and cell suspensions. New innovations proposed are the systemic integration of MRI as a surrogate marker with flow cytometry techniques, electron microscopy, electron paramagnetic spectroscopy and high performance liquid chromatography into the unique animal model to probe the biochemical basis of two forms of cell death. These studies will elucidate the early events around critical cell death that cause motor deficits. The clinical importance is that the proposed studies provides the mechanistic understanding for the systematic development of much-needed therapies for CP, and thus expedites the clinical application of these therapies.

项目总结/摘要 脑性瘫痪（CP）是一种严重的疾病，通常起源于出生前的缺氧缺血（H-I）。它 由于对患者的终身影响，它具有最高的疾病负担指数之一， 照顾者和社会机构。社会的成本是巨大的，高达115亿美元，不包括 社会中潜在生产力成员的流失。预防一名CP患者将节省近1.2美元 100万美元，不考虑CP儿童的年轻父母的生产力损失。受影响的CP数量 美国有800，000名患者，疾病负担高于许多影响美国的成人神经系统疾病 暮年然而，对于CP缺乏有效的治疗方法。CP缺乏进展， 可能是因为缺乏足够的分配资源，缺乏临床相关的动物模型和 缺乏系统的方法来解决这个问题。本提案涉及后两个问题。我们将使用 早产时急性胎盘功能不全后形成的CP兔模型，基于 人类胎盘炎这个H-I模型是第一个可靠地导致CP的模型，允许我们严格地 不仅测试机制途径，而且测试目前没有可用的CP的可能疗法。 我们已经鉴定了旨在抑制神经元型一氧化氮合酶（nNOS）的新型药物，并表明， 这些药物在产前给药时可预防兔的CP。我们还表明，产前抗氧化剂 同样也能预防CP。随着MRI替代标记物的开发，我们可以预测哪些胎儿 会出现产后运动缺陷在H-I中，细胞死亡以多种形式发生，包括两种形式， 特别是涉及氧化剂，称为坏死性凋亡和铁凋亡。这项建议提出的主要问题是 氧化剂引发的两种形式的细胞死亡是否会导致运动缺陷的发展。第一 目的是确定哪些形式的细胞死亡与运动缺陷密切相关。的 第二个目标将确定氧化剂是否触发导致运动缺陷的细胞死亡的关键形式。的 潜在的生化机制将利用胎儿的鉴定来研究， 出生后高张力和研究整个大脑，大脑区域和细胞悬浮液。提议的新创新 是MRI作为替代标记物与流式细胞术技术，电子显微镜， 电子顺磁光谱和高效液相色谱分析到独特的动物 模型来探索两种形式的细胞死亡的生化基础。这些研究将阐明早期事件 导致运动缺陷的关键细胞死亡临床重要性在于， 为CP急需的治疗方法的系统开发提供了机制上的理解， 从而加快这些疗法的临床应用。