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

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元离子稳态，GABA信号传导和 30年的癫痫病史这种持续的支持使一个成功的板凳完成- 床旁翻译的新生儿癫痫发作的新疗法，这在很大程度上是没有反应的可用 治疗这种新疗法是基于操纵神经元阴离子稳态，这有助于 GABAA受体信号传导和容量调节。这些研究使我们认识到 细胞内外阴离子大分子对神经元氯离子和体积的唐南效应 体内平衡细胞内和细胞外离子和渗透力之间的微妙平衡可以很容易地 由于膜渗透性的变化或膜一侧渗透压摩尔的移动而扰乱。这里 我们认为，脑损伤会导致这两种扰动，从而对大脑造成灾难性的影响。 神经元容量调节在成熟的大脑中，这会导致细胞毒性水肿和脑肿胀， 没有治愈性的，只有适度有效的对症治疗。在早产儿的大脑中， 量的变化也同样有问题，但我们的分析预测它们的符号相反。我们 提出未成熟的神经元在损伤后收缩，导致缺乏MRI DWI特征以及局部 组织收缩血管伸展和潜在出血这些影响有助于当前 在照顾极低出生体重婴儿的问题：脑损伤是猖獗的，但直接原因是 不清楚，因为损伤不能用MRI或超声成像。只有后果 （出血和萎缩）可见。我们建议调查神经元离子和体积的变化后，损伤 在体外和体内，使用先进的成像技术和离子敏感的荧光团。结果将 提供了强有力的指标，以确定这些对受损神经元体积变化的新见解是否已经准备就绪 转化为新的治疗策略，用于发育和成熟的受损大脑。