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

• 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
• 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

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).

摘要 治疗性低温（TH）可改善CNS损伤后的神经功能结局。临床前研究表明 温和冷却至~33°C对涉及多种机制的受伤大脑有有益影响 包括（但不限于）：发热减轻，代谢需求/ATP消耗减少， 细胞凋亡的细胞内介质和增加促存活蛋白。相比之下，TH还可以增加 不良并发症的风险，如感染、离子紊乱、高血糖和胰岛素抵抗， 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)无论是儿童还是成人。最近的临床试验是为了比较 与使用目标温度预防发热相比，在使用轻度TH至33°C治疗的心脏骤停患者中效果更好 管理（TTM）至~36°C。没有观察到神经学结果的差异-表明TH和 TTM疗效相似。两个治疗组的发热抑制可以解释这些令人惊讶的结果。 研究结果;众所周知，发烧1-2°C会使神经系统结果急剧恶化。鉴于双方 温度提供了类似的好处，因为TTM的应用与较少的不良反应有关， TTM可能是最安全的体温管理治疗选择。反之，a TTM的主要局限性是它不被认为激活额外的神经保护机制（如TH）。 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）减少全身副作用的药物 TH的神经保护作用。该R21将测试成纤维细胞生长因子21（FGF 21）是否增加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（RBM 3）。