Neuronal ion and volume shifts after acute brain injury

急性脑损伤后神经元离子和体积变化

• 批准号: 10392372
• 负责人: Kevin J. Staley
• 金额: $ 122.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392372
• 关键词: Acute Brain Injuries; Anions; Atrophic; Blood Vessels; Brain; Brain Edema; Brain Injuries; Caring; Cell Membrane Permeability; Chlorides; Diffusion Magnetic Resonance Imaging; Edema; Epileptogenesis; Equilibrium; Funding; Hemorrhage; Homeostasis; Image; Imaging Techniques; In Vitro; Injury; Investments; Ions; Low Birth Weight Infant; Magnetic Resonance Imaging; Membrane; National Institute of Neurological Disorders and Stroke; Neuronal Injury; Neurons; Receptor Signaling; Regulation; Seizures; Side; Signal Transduction; Stretching; Tissues; Translating; Translations; base; bench-to-bedside translation; brain volume; career; clinical care; cytotoxic; extracellular; fluorophore; gamma-Aminobutyric Acid; improved outcome; in vivo; infant brain injury; insight; macromolecule; neonatal seizure; novel therapeutic intervention; novel therapeutics; premature; ultrasound; Acute Brain Injuries; Anions; Atrophic; Blood Vessels; Brain; Brain Edema; Brain Injuries; Caring; Cell Membrane Permeability; Chlorides; Diffusion Magnetic Resonance Imaging; Edema; Epileptogenesis; Equilibrium; Funding; Hemorrhage; Homeostasis; Image; Imaging Techniques; In Vitro; Injury; Investments; Ions; Low Birth Weight Infant; Magnetic Resonance Imaging; Membrane; National Institute of Neurological Disorders and Stroke; Neuronal Injury; Neurons; Receptor Signaling; Regulation; Seizures; Side; Signal Transduction; Stretching; Tissues; Translating; Translations; base; bench-to-bedside translation; brain volume; career; clinical care; cytotoxic; extracellular; fluorophore; gamma-Aminobutyric Acid; improved outcome; in vivo; infant brain injury; insight; macromolecule; neonatal seizure; novel therapeutic intervention; novel therapeutics; premature; ultrasound

The NINDS has provided me the opportunity to study neuronal ion homeostasis, GABA signaling, and epileptogenesis for 30 years. That sustained support enabled the completion of a successful bench-to- bedside translation of a new therapy for neonatal seizures, which are largely unresponsive to available therapies. This new therapy is based on manipulation of neuronal anion homeostasis, which subserves both GABAA receptor signaling and volume regulation. These studies led us to appreciate the magnitude of the Donnan effects of intra and extracellular anionic macromolecules on neuronal chloride and volume homeostasis. The delicate balance between intra and extracellular ionic and osmotic forces could be easily upset by changes in membrane permeability or mobilization of osmoles on one side of the membrane. Here we propose that brain injury results in both of these perturbations, with consequent catastrophic effects on neuronal volume regulation. In the mature brain, this results in cytotoxic edema and brain swelling, for which there are no curative and only modestly effective symptomatic therapies. In the premature brain, volume changes are equally problematic, but our analyses predict that they are opposite in sign. We propose that immature neurons shrink after injury, resulting in an absent MRI DWI signature as well as local tissue shrinkage, vascular stretch, and potential hemorrhage. These effects contribute to the current problems in the care of very low birthweight infants: brain injury is rampant, but the immediate causes are not clear because the injury cannot be imaged with MRI or ultrasound. Only the consequences (hemorrhage and atrophy) are visible. We propose to investigate neuronal ion and volume shifts after injury in vitro and in vivo, using advanced imaging techniques and ion-sensitive fluorophores. The results will provide robust indicators as to whether these new insights into volume shifts in injured neurons are ready for translation to novel therapeutic strategies for both the developing and the mature injured brain.

Ninds为我提供了研究神经离子稳态，GABA信号和 癫痫发生30年。持续的支持使得成功的基准完成了 新生儿癫痫发作的新疗法的床头翻译，这在很大程度上没有反应 疗法。这种新疗法是基于对神经阴离子稳态的操纵 GABAA受体信号传导和体积调节。这些研究使我们欣赏了 细胞内和细胞外阴离子大分子对神经元氯化物和体积的唐南作用 稳态。细胞内离子和渗透力之间的微妙平衡很容易被很容易 因膜上渗透性的变化或动员膜上的一侧动员而感到沮丧。这里 我们提出脑损伤会导致这两种扰动，从而对 神经元体积调节。在成熟的大脑中，这会导致细胞毒性水肿和脑肿胀，因为 没有治愈性，只有适度有效的症状疗法。在过早的大脑中， 体积变化同样有问题，但是我们的分析预测它们在符号上是相反的。我们 建议未成熟的神经元在受伤后收缩，导致缺乏MRI DWI签名以及局部 组织收缩，血管拉伸和潜在出血。这些影响有助于当前 护理非常低的出生体重婴儿的问题：脑损伤猖ramp，但直接的原因是 不清楚，因为无法使用MRI或超声检查对伤害进行成像。只有后果 （出血和萎缩）是可见的。我们建议在受伤后研究神经元离子和体积变化 使用先进的成像技术和对离子敏感的荧光团的体外和体内。结果将 关于这些新的对受伤神经元体积变化的新见解是否已准备就绪，提供了强有力的指标 为了转化为发育中和成熟受伤的大脑的新型治疗策略。