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

基本信息

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
项目类别：
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

项目摘要

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： Umeshkumar Athiraman博士医学博士是一位神经科学家和神经刺杀科医生，其长期目标是独立研究者专注于理解麻醉条件的潜在机制 - 诱导神经血管保护，开发基于麻醉的动脉瘤的疗法亚蛛网膜下腔出血（SAH），然后将这些见解应用于其他形式的脑损伤。博士 Athiraman是Saint Washington University神经外科Zipfel博士实验室的成员路易。实验室，系和大学提供了出色的培训环境。 Athiraman Will博士在SAH动物模型，免疫组织化学，分子生物学技术的Zipfel实验室接受培训 SAH后的短期和长期神经行为结局的评估。他还将接受培训合作者Adam Bauer博士实验室中的功能连通性评估的光学成像。额外的申请人的麻醉学部门将提供支持和心态。 SAH是严重的出血性中风的类型，发病率和死亡率极高。除了最初的出血严重程度外，由于脑缺血延迟引起的继发性脑损伤（DCI）在患者结局中起着重要作用 SAH。虽然在临床前研究中已经制定了许多打击DCI的策略，并在后期进行了测试临床试验，没有事实证明有效地改善了长期功能结果。这些原因失败可能是众多多因素脑损伤过程。拟议的项目研究了已知的疗法的影响 SAH称为 - 调理（麻醉）后，对DCI的强大，多方面的保护作用。初步的数据表明，异氟烷调节为SAH诱导的DCI提供了强大的保护，这是保护可能是通过抑制两个关键分子-NF-KB和iNOS来介导的。计划的实验将通过针对目标的遗传和药物干预措施严格检验以下假设：1） NF-KB的抑制作用是异氟烷调节提供的DCI保护； 2）抑制iNOS（关键 NF-KB的下游靶标是异氟烷调节提供的DCI保护的基础； 3）毒品模拟异氟烷调节（NF-KB抑制剂，PDTC-吡咯烷二硫代氨酸；和 iNOS抑制剂，1400W）可长期保护神经行为和功能连通性缺陷 SAH之后。这些实验的结果将从根本上建立NF-KB/INOS途径抑制作用作为在SAH中诱导的异氟烷调节诱导的DCI保护的关键诱导剂，并识别NF-KB/Inos抑制作用有希望的SAH新治疗策略。拟议的计划将为Athiraman博士提供培训，识别和经验及时过渡到独立并获得R01资金。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
作者：
通讯作者：

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