Neuroprotection by nNOS inhibitors in perinatal hypoxia-ischemia

nNOS 抑制剂对围产期缺氧缺血的神经保护作用

基本信息

批准号：
10651613
负责人：
SIDHARTHA TAN
金额：
$ 61.87万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651613
关键词：
Abbreviations Abruptio Placentae Acute Adult Affect Animal Model Antioxidants Area Axon Biochemical Birth Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Cell Culture Techniques Cell physiology Cerebral Palsy Childhood Cholera Toxin Clinical Clinical Trials Communities Country Dancing Developed Countries Development Diffusion Disease Dose Electron Spin Resonance Spectroscopy Electrophysiology (science)Endoplasmic Reticulum Endothelium Enzyme Inhibition Equation Ethidium Facilities and Administrative Costs Family Fetal Distress Fetus Fiber Financial cost Free Radicals Future Generations Genetic High Pressure Liquid Chromatography Human Injury Laboratories Location Magnetic Resonance Imaging Measures Methodology Modeling Molecular Morbidity - disease rate Mothers Motor Muscle Hypertonia Nature Neuronal Injury Neurons Neuroprotective Agents Nitric Oxide Nitric Oxide Synthase Type I Nitric Oxide Synthetase Inhibitor Nitrogen Oxides Oryctolagus cuniculus Outcome Oxidants Oxidation-Reduction Oxidative Stress Parents Pathway interactions Patients Perinatal Perinatal Hypoxia Pharmaceutical Preparations Phase Phenotype Placental Insufficiency Pregnancy Premature Labor Prevalence Prevention Prevention therapy Preventive Property Propidium Diiodide Reactive Nitrogen Species Reactive Oxygen Species Reperfusion Therapy Resource-limited setting Resources Rhodamine 123 Rodent Model Siblings Societies Sorting Specificity Speed Stress Sum Superoxide Dismutase Superoxides Surrogate Markers System Techniques Testing Therapeutic Time Tissues Translating Translations Western Blotting antenatal brain cell burden of illness cell injury cost disability drug action drug candidate effective therapy fetal gray matter hydroethidine in vivo indexing inhibitor innovation interest magnetic resonance imaging biomarker mortality motor deficit neonatal hypoxic-ischemic brain injury nervous system disorder neuroprotection nitrosative stress novel novel therapeutics oxidation perinatal period postnatal prevent response severe injury white matter white matter injury

项目摘要

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. The costs to society are huge, to the tune of $15 billion. Prevention of a single CP patient would save almost $1.2 million dollars, not factoring indirect costs to parents, siblings, communities and society from life-long commitments. 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. To solve the problems of finding new neuroprotectants that can be translated to the humans situation, we are proposing to test novel specific inhibitors of neuronal nitric oxide synthase (nNOS) in a rabbit model of cerebral palsy based on human acute placental insufficiency and the clinical paradigm of placental abruption. These new nNOS inhibitors are the most potent neuroprotectants found in our laboratory. We utilize MRI biomarkers that inform us about the immediate fetal brain response to H-I and reliably predict which rabbit fetuses will manifest motor deficits after delivery. We utilize recent advances in detecting oxidative and nitrosative stress (caused by reactive nitrogen species derived from nitric oxide). Instead of a zero-sum way of looking at oxidative stress and antioxidants, we posit the biphasic nature of reactive species in brain cell function and that a dance between various oxidants and antioxidants is necessary for critical brain injury. We hypothesize that the timing and location of nitrosative stress in important in determining which fetuses will develop motor deficits. The proposed studies will lead to the development of a neuroprotective strategy that can also be used in resource-poor countries in addition to developed countries. The first Aim will determine the nature of gray and white matter injury in the fetal brain. The second Aim will determine whether nitric oxide derived from nNOS is responsible for the critical brain injury that results in motor deficits. The third Aim will determine the best candidate drug to take to clinical trials. The new innovations proposed are the systemic integration of MRI as a surrogate marker and high speed sorting into the unique animal model to probe the biochemical basis of specific neuronal injury at a critical time point. The clinical importance of this proposal is that the studies will select the most potent and non-toxic drug in the class of nNOS inhibitors for preventing motor deficits. The proposed studies will thus provide the systematic development of much-needed therapies for CP not only in USA but throughout the world.

项目概要/摘要脑瘫（CP）是一种破坏性疾病，通常起源于出生前的缺氧缺血（H-I）。它是疾病负担指数最高的国家之一。社会成本高达 15 美元十亿。预防一名 CP 患者可节省近 120 万美元，这还不包括间接成本父母、兄弟姐妹、社区和社会的终身承诺。受影响的脑瘫患者数量，美国有 800,000 人，疾病负担比许多影响暮光的成人神经系统疾病还要高年。然而，脑瘫的有效治疗方法却很缺乏。解决寻找新的问题可以转化为人类情况的神经保护剂，我们建议测试新的特异性基于人急性脑瘫兔模型的神经元一氧化氮合酶（nNOS）抑制剂胎盘功能不全和胎盘早剥的临床范例。这些新的 nNOS 抑制剂是我们实验室发现的最有效的神经保护剂。我们利用 MRI 生物标志物来告知我们胎儿大脑对 H-I 的即时反应，并可靠地预测哪些兔子胎儿在 H-I 后会表现出运动缺陷送货。我们利用最新进展来检测氧化和亚硝化应激（由活性氮引起）源自一氧化氮的物种）。不是以零和的方式看待氧化应激和抗氧化剂，我们假设脑细胞功能中活性物质具有双相性质，并且各种物质之间存在舞蹈氧化剂和抗氧化剂对于严重的脑损伤是必需的。我们假设发生的时间和地点亚硝化应激对于确定哪些胎儿会出现运动缺陷很重要。拟议的研究将导致神经保护策略的制定，该策略也可用于资源匮乏的国家除了发达国家。第一个目标将确定灰质和白质损伤的性质胎儿的大脑。第二个目标将确定源自 nNOS 的一氧化氮是否是导致这一关键事件的原因。导致运动缺陷的脑损伤。第三个目标将确定进入临床的最佳候选药物试验。提出的新创新是将 MRI 作为替代标记和高快速分类成独特的动物模型，以探究特定神经元损伤的生化基础关键时间点。该提案的临床重要性在于，研究将选择最有效和最有效的用于预防运动缺陷的 nNOS 抑制剂类无毒药物。因此，拟议的研究将不仅在美国而且在整个国家提供急需的脑瘫治疗方法的系统开发世界。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A systematic review of noninflammatory cerebrospinal fluid biomarkers for clinical outcome in neonates with perinatal hypoxic brain injury that could be biologically significant.

对非炎症性脑脊液生物标志物对围产期缺氧性脑损伤新生儿临床结果的系统评价可能具有生物学意义。

DOI：
发表时间：
2022-12
期刊：
影响因子：
4.2
作者：
Shi, Zhongjie;Luo, Kehuan;Deol, Saihaj;Tan, Sidhartha
通讯作者：
Tan, Sidhartha

Neuroprotective therapies in the NICU in term infants: present and future.

NICU 足月婴儿的神经保护疗法：现在和未来。

DOI：
发表时间：
2023-06
期刊：
影响因子：
3.6
作者：
Molloy, Eleanor J;El;Juul, Sandra E;Benders, Manon;Gonzalez, Fernando;Bearer, Cynthia;Wu, Yvonne W;Robertson, Nicola J;Hurley, Tim;Branagan, Aoife;Michael Cotten, C;Tan, Sidhartha;Laptook, Abbot;Austin, Topun;Mohammad, Khorshid
通讯作者：
Mohammad, Khorshid

Tetrahydrobiopterin in Cell Function and Death Mechanisms.

四氢生物蝶呤在细胞功能和死亡机制中的作用。