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FGF21 Activates RBM3 and is a Novel Drug to Revolutionize Temperature Management

FGF21激活RBM3，是彻底改变温度管理的新药

基本信息

批准号：
9314031
负责人：
TRAVIS C JACKSON
金额：
$ 23.23万
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：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314031
关键词：
Acute Brain Injuries Adaptor Signaling Protein Adult Adverse effects Animals Apoptosis Blood - brain barrier anatomy Brain Brain Injuries Cause of Death Cerebellum Child Childhood Clinical Trials Consumption Contusions Data Development Disadvantaged Exposure to Fever Fibroblast Growth Factor Receptors Heart Arrest Hibernation Hippocampus (Brain)Hormones Hyperglycemia Impairment In Vitro Infection Injury Insulin Resistance Ions Ischemia Legal patent Mediating Mediator of activation protein Medical Metabolic Methods Modeling Mus Neurodegenerative Disorders Neurologic Neurological outcome Neurons Patients Penetration Pharmaceutical Preparations Pharmacology Prevention Proteins RNA Binding RNA Interference RNA-Binding Proteins Rattus Receptor Activation Reporting Risk Seminal Signal Transduction Synapses Temperature Testing Therapeutic Therapeutic Effect Time Translating Traumatic Brain Injury Treatment Efficacy Up-Regulation behavioral outcome central nervous system injury cold shock protein controlled cortical impact disability fibroblast growth factor 21 improved improved outcome in vitro testing in vivo induced hypothermia innovation mortality natural hypothermia neonate neuronal survival neuroprotection novel novel therapeutics pediatric traumatic brain injury postnatal preclinical study receptor treatment group

项目摘要

ABSTRACT Therapeutic hypothermia (TH) improves neurologic outcomes after CNS injury. Preclinical studies show that mild cooling to ~33°C has beneficial effects on the injured brain which involves multiple mechanisms including (but not limited to): fever reduction, decreasing metabolic demand/ATP consumption, decreasing intracellular mediators of apoptosis, and increasing pro-survival proteins. In contrast, TH can also increase the risk of adverse complications like infection, ion disturbances, hyperglycemia, and insulin resistance – which may increase mortality or worsen brain injury. TH surprisingly has failed to translate in traumatic brain injury (TBI) in either children or adults. Recent clinical trials were done to compare if neurological outcomes were better in cardiac arrest patients treated with mild TH to 33°C vs. fever prevention using targeted temperature management (TTM) to ~36°C. No difference in neurological outcome was observed - indicating that TH and TTM had similar therapeutic efficacy. Inhibition of fever in both treatment groups may explain those surprising findings; fever by as little as 1-2°C is well known to dramatically worsen neurologic outcomes. Given that both temperatures provided similar benefits, and because the application of TTM is associated with fewer adverse side effects than TH, TTM may be the safest therapeutic option for temperature management. Conversely, a key limitation of TTM is that it is not thought to activate additional neuroprotective mechanisms (as does TH). The next advance in temperature management therapy may be to discover drugs which make TTM more neuroprotective (Concept 1), or alternatively (Concept 2) drugs which lessen the systemic side effects of neuroprotective TH. This R21 will test if fibroblast growth factor 21 (FGF21) augments TTM/TH induced neuroprotection in a rat model of pediatric TBI, in part, by upregulating the highly neuroprotective cold- shock protein RNA binding motif 3 (RBM3).

抽象的低温治疗 (TH) 可改善中枢神经系统损伤后的神经系统预后。临床前研究表明温和冷却至约 33°C 对受伤的大脑有有益的影响，这涉及多种机制包括（但不限于）：退烧、减少代谢需求/ATP 消耗、减少细胞内凋亡介质，并增加促生存蛋白。相比之下，TH 也可以增加感染、离子紊乱、高血糖和胰岛素抵抗等不良并发症的风险可能会增加死亡率或加重脑损伤。令人惊讶的是，TH 未能转化为创伤性脑损伤 (TBI) 发生在儿童或成人中。最近进行的临床试验是为了比较神经学结果是否对于心脏骤停患者，采用轻度 TH 至 33°C 治疗比使用目标温度预防发烧效果更好管理 (TTM) 至 ~36°C。没有观察到神经系统结果的差异 - 表明 TH 和 TTM具有相似的治疗效果。两个治疗组中发烧的抑制可能解释了那些令人惊讶的现象发现;众所周知，仅 1-2°C 的发烧就会显着恶化神经系统结果。鉴于两者温度提供了类似的好处，并且因为 TTM 的应用与较少的不良反应相关相比 TH 的副作用，TTM 可能是温度管理最安全的治疗选择。相反，一个 TTM 的主要限制是它不会激活额外的神经保护机制（TH 也是如此）。温度管理疗法的下一个进展可能是发现使 TTM 更多的神经保护（概念 1），或者（概念 2）减轻全身副作用的药物 TH 的神经保护作用。该 R21 将测试成纤维细胞生长因子 21 (FGF21) 是否增强 TTM/TH 在儿童 TBI 大鼠模型中诱导神经保护，部分是通过上调高度神经保护性的冷- 休克蛋白 RNA 结合基序 3 (RBM3)。