Molecular mechanisms underlying isoflurane conditioning-induced neurovascular protection in subarachnoid hemorrhage

异氟烷调理诱导蛛网膜下腔出血神经血管保护的分子机制

• 批准号: 10665043
• 负责人: Umeshkumar Athiraman
• 金额: $ 17.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665043
• 关键词: Acute; Anesthesiology; Anesthetics; Aneurysmal Subarachnoid Hemorrhages; Angiography; Animal Model; Arteries; Attenuated; Automobile Driving; B-Cell Activation; Behavioral; Biochemical; Biological; Brain; Brain Injuries; Brain hemorrhage; Cerebral Ischemia; Clinical Trials; Complement; Data; Development; Distal; Down-Regulation; Elements; Emotional; Enhancers; Environment; Failure; Functional disorder; Funding; Genetic; Goals; Health; Hemorrhage; I-kappa B Proteins; Image; Immunohistochemistry; Impaired cognition; Impairment; Inflammation; Intervention; Isoflurane; Knowledge; Light; Mediating; Mentorship; Methods; Microglia; Molecular; Molecular Biology Techniques; Molecular Target; Morbidity - disease rate; Mus; NF-kappa B; NOS2A gene; Neurologic Deficit; Nitric Oxide Synthetase Inhibitor; Nuclear; Optics; Outcome; Outcome Assessment; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Physicians; Pilot Projects; Play; Preclinical Testing; Process; Quality of life; Research Personnel; Rodent Model; Role; Scientist; Severities; Signal Transduction; Source; Subarachnoid Hemorrhage; Survivors; Techniques; Testing; Therapeutic; Thrombosis; Thrombus; Training; Translating; Universities; Vasospasm; Volatilization; Washington; Work; combat; conditioning; experience; experimental study; functional outcomes; functional status; genomic tools; halogenation; improved; improved outcome; in vivo; inducible gene expression; innovation; insight; member; mortality; mouse model; neurobehavioral; neurosurgery; neurovascular; new therapeutic target; novel; novel therapeutic intervention; optical imaging; overexpression; pharmacologic; preclinical study; prevent; protective effect; protein expression; pyrrolidine dithiocarbamate; skills; targeted treatment; therapeutic target; tool; transcription factor; translational potential

Abstract/Project Summary: Dr. Umeshkumar Athiraman MD, is a neuroscientist and neuroanesthesiologist with the long-term goal to be an independent investigator focused on understanding the underlying mechanisms of anesthetic conditioning- induced neurovascular protection, development of anesthetic conditioning-based therapeutics for aneurysmal subarachnoid hemorrhage (SAH), and later application of these insights to other forms of brain injury. Dr. Athiraman is a member of Dr. Zipfel’s lab in the Department of Neurosurgery at Washington University in Saint Louis. The lab, department, and the university provide an exceptional training environment. Dr. Athiraman will receive training in the Zipfel lab in SAH animal models, immunohistochemistry, molecular biology techniques and assessment of short and long-term neurobehavioral outcomes after SAH. He will also receive training in optical imaging for functional connectivity assessment in the lab of collaborator, Dr. Adam Bauer. Additional support and mentorship will be provided by the applicant’s host department of anesthesiology. SAH is a severe type of hemorrhagic stroke with extremely high morbidity and mortality. Apart from the initial hemorrhage severity, secondary brain injury due to delayed cerebral ischemia (DCI) plays a significant role in patient outcomes after SAH. While many strategies to combat DCI have been developed in preclinical studies and tested in late phase clinical trials, none have proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. The proposed project examines the impact of a therapy known to have powerful, multifaceted protective effects on DCI after SAH called as – conditioning (anesthetic). Preliminary data shows that isoflurane conditioning provides robust protection against SAH-induced DCI and that this protection is likely mediated via inhibition of two critical molecules – NF-kB and iNOS. The planned experiments will rigorously test the following hypothesis through targeted genetic and pharmacological interventions: 1) Inhibition of NF-kB underlies the DCI protection afforded by isoflurane conditioning; 2) Inhibition of iNOS (a key downstream target of NF-kB) underlies the DCI protection afforded by isoflurane conditioning; and 3) Drugs that mimic the molecular effects of isoflurane conditioning (NF-kB inhibitor, PDTC-pyrrolidine dithiocarbamate; and iNOS inhibitor, 1400W) provide long-term protection against neurobehavioral and functional connectivity deficits after SAH. The results of these experiments will fundamentally establish NF-kB/iNOS pathway inhibition as the key inducer of isoflurane conditioning-induced DCI protection in SAH and identify NF-kB/iNOS inhibition as a promising new therapeutic strategy for SAH. The proposed plan will provide Dr. Athiraman with the training, mentorship and experience to transition to independence in a timely manner and obtain R01 funding.

摘要/项目摘要： 博士医学博士Umeshkumar Athioman是一位神经科学家和神经麻醉学家，其长期目标是成为一名神经外科医生。 独立研究者专注于了解麻醉条件反射的潜在机制- 诱导的神经血管保护，基于麻醉条件的治疗方法的发展， 蛛网膜下腔出血（SAH），以及后来将这些见解应用于其他形式的脑损伤。博士 Athienis是位于圣路易斯的华盛顿大学神经外科系Zipfel博士实验室的一员 Louis.实验室，部门和大学提供了一个特殊的培训环境。亚瑟博士会 在Zipfel实验室接受SAH动物模型，免疫组织化学，分子生物学技术的培训 并评估SAH后的短期和长期神经行为结果。他还将接受培训， 在合作者Adam Bauer博士的实验室中进行功能连接评估的光学成像。额外 申请人所在的麻醉科将提供支持和指导。SAH是严重的 出血性脑卒中，发病率和死亡率极高。除了最初的出血严重程度， 由于迟发性脑缺血（DCI）引起的继发性脑损伤对患者的预后起着重要作用， SAH。虽然许多对抗DCI的策略已经在临床前研究中开发并在后期测试 临床试验中，没有一个被证明对改善长期功能结果有效。产生的原因 失败可能是多方面的，但包括使用仅针对已被证明是 多因素脑损伤过程。拟议的项目研究了一种已知的治疗方法的影响， 对蛛网膜下腔出血后的DCI具有强大的、多方面的保护作用，称为条件反射（麻醉剂）。初步 数据显示，异氟烷预处理对SAH诱导的DCI提供了强有力的保护， 保护作用可能是通过抑制两种关键分子NF-κ B和iNOS介导的。计划中的实验 将通过有针对性的遗传和药理干预来严格检验以下假设：1） NF-kB的抑制是异氟醚预处理提供的DCI保护的基础; 2）iNOS的抑制（一个关键因素）， NF-kB的下游靶点）是异氟烷调节提供的DCI保护的基础;和3） 模拟异氟烷调节的分子效应（NF-κ B抑制剂，PDTC-吡咯烷二硫代氨基甲酸酯;和 iNOS抑制剂，1400 W）提供长期保护，防止神经行为和功能连接缺陷 SAH后。这些实验的结果将从根本上确立NF-kB/iNOS途径抑制作为 异氟醚预处理诱导DCI保护SAH的关键诱导剂，并将NF-kB/iNOS抑制确定为 有希望的SAH新治疗策略。拟议中的计划将为Athiovane博士提供培训， 指导和经验，以及时过渡到独立，并获得R 01资金。

项目成果

A Global Review of the Perioperative Care of Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Microsurgical Repair of Ruptured Intracerebral Aneurysm.

对接受显微外科修复破裂脑内动脉瘤的动脉瘤性蛛网膜下腔出血患者围手术期护理的全球回顾。

• DOI: 10.1097/ana.0000000000000913
• 发表时间: 2024
• 期刊: Journal of neurosurgical anesthesiology
• 影响因子: 3.7
• 作者: Lele,AbhijitV;Shiferaw,AnanyaAbate;Theard,MarieAngele;Vavilala,MonicaS;Tavares,Cristiane;Han,Ruquan;Assefa,Denekew;DagneAlemu,Mihret;Mahajan,Charu;Tandon,MonicaS;Karmarkar,NeetaV;Singhal,Vasudha;Lamsal,Ritesh;Athiraman,Um
• 通讯作者: Athiraman,Um

Propofol Affords No Protection against Delayed Cerebral Ischemia in a Mouse Model of Subarachnoid Hemorrhage.

• DOI: 10.3390/diseases11040130
• 发表时间: 2023-09-27
• 期刊: Diseases (Basel, Switzerland)

Anesthesiology Performance Improvement and Reporting Exchange (ASPIRE) Quality Metrics in Patients Undergoing Decompressive Craniectomy and Endoscopic Clot Evacuation after Spontaneous Supratentorial Intracerebral Hemorrhage: A Retrospective Observational

自发性幕上脑出血后接受去骨瓣减压术和内镜下血块清除术的患者的麻醉学表现改进和报告交换 (ASPIRE) 质量指标：回顾性观察

• DOI: 10.1097/ana.0000000000000912
• 发表时间: 2023
• 期刊: Journal of neurosurgical anesthesiology
• 影响因子: 3.7
• 作者: Lele,AbhijitV;Fong,ChristineT;Newman,Shu-Fang;O'Reilly-Shah,Vikas;Walters,AndrewM;Athiraman,Umeshkumar;Souter,MichaelJ;Levitt,MichaelR;Vavilala,MonicaS
• 通讯作者: Vavilala,MonicaS