Reducing Infection Susceptibility by Immune Function Restoration in Spinal Cord Injury

通过恢复脊髓损伤的免疫功能来降低感染易感性

基本信息

批准号：
10656433
负责人：
Jan Schwab
金额：
$ 36.76万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656433
关键词：
Acute Acute Pneumonia Address Adrenal Gland Hyperfunction Adrenal Glands Anatomy Anti-Infective Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Applications Grants Atrophic Autonomic Dysfunction Bacteria Bacterial Pneumonia Biological Assay Biological Markers Catecholamines Cause of Death Cells Cessation of life Characteristics Clinical Colony-forming units Complement Cre lox recombination system Data Development Disinhibition Drug Delivery Systems Dysautonomias Endocrine Experimental Models FDA approved Failure Functional disorder Ganglia Genetic Goals Host Defense Immune Immune system Immunologic Deficiency Syndromes Immunosuppression Impairment Individual Infection Infection prevention Injury Intervention Lesion Life Lung Lymphocyte Count Lymphoid Tissue Lymphopenia Methodology Molecular Target Multicenter Studies Nerve Neurologic Neurons Neurosecretory Systems Nosocomial pneumonia Outcome Pathogenesis Pathologic Patients Pharmaceutical Preparations Pneumonia Predisposition Prevention Qualifying Recovery Recovery of Function Reflex action Regimen Risk Risk Factors Sepsis Series Severities Site Spinal Spinal cord injury Spinal cord injury patients Spleen Streptococcus pneumoniae Sympathetic Nerve Block Synaptic Transmission T-Lymphocyte Technology Testing Thymus Gland Tissues Vertebral column Whole Blood adverse outcome cholinergic clinical application clinically relevant disability drug repurposing experimental study gabapentin gut dysbiosis immune function immune system function improved in vivo insight modifiable risk mortality neurological recovery neuroregulation novel pharmacologic presynaptic prevent restoration septic transmission process treatment strategy voltage

项目摘要

Abstract Acquired infections after spinal cord injury (SCI) are prevalent, constitute the main cause of death in patients and have been identified as a modifiable risk factor associated with poor neurological and functional recovery. Infection treatment by orthodox antibiotics is complicated by i) spectrum/efficacy gaps, ii) early development of antibiotic resistancies, and iii) failure of antibiotics to prevent infections when applied early in patients with acute CNS lesions. Moreover, new evidence indicates that antibiotics can impair neurological recovery, due to their ability to cause gut dysbiosis. Improved anti-infective treatment strategies are critically needed, which take the immune-compromised status after SCI into account. Recent data have identified unregulated sympathetic tone originating from below the spinal cord injury site (spinally generated sympathetic nerve activity, SNA) as a major driver of the systemic spinal cord injury immune deficiency syndrome (SCI-IDS). SNA has been identified and independently confirmed as a mechanistic target to restore immune function in vivo. Three aims are proposed to answer one main and novel question: Can immune function and host-defense against pneumonia be re-established with SNA-targeting immunotrophic pharmacological neuromodulation (IPN)? Experiments in Aim 1 will use a novel combination of FDA-approved drugs selected to promote immune system function and reduce susceptibility to bacterial pneumonia acutely or at 4 weeks post SCI. Aim 2 will assess the capacity of IPN to normalize different cellular SCI-IDS characteristics and the sympathetic neuroendocrine reflex. Irrespective of SCI, infections are well-known causes of dysautonomia, which is a pathophysiological conduit for septic conversions. Aim 3 addresses whether IPN can blunt infection-associated autonomic dysfunction and neutralize a sepsis risk factor. If successful, data from these experiments will directly inform effective non-antibiotic anti-infective strategies for SCI patients to reduce infection-associated mortality and disability.

抽象的脊髓损伤后获得的感染（SCI）普遍存在，构成患者的主要原因并被确定为与不良神经和功能恢复相关的可修改风险因素。正统抗生素的感染治疗因i）频谱/功效差距而复杂，ii）早期发展在急性中枢神经系统病变。此外，新的证据表明抗生素会损害神经系统恢复它们引起肠道营养不良的能力。迫切需要改善的反感染治疗策略，这需要 SCI后的免疫功能障碍状态。最近的数据已经确定了不受管制的同情心音调起源于脊髓损伤部位下方（旋转产生的交感神经活动，SNA）全身性脊髓损伤免疫缺陷综合征（SCI-IDS）的主要驱动力。 SNA曾经鉴定并独立确认为恢复体内免疫功能的机械靶标。三个目标提议回答一个主要和新颖的问题：可以免疫功能和宿主防御通过靶向SNA的免疫营养性神经调节（IPN）重新建立肺炎？ AIM 1中的实验将使用选择促进免疫的FDA批准药物的新型组合系统功能并降低对细菌性肺炎的敏感性急性或科学后4周。 AIM 2意志评估IPN标准化不同细胞SCI-IDS特征和交感神经的能力神经内分泌反射。不论SCI如何，感染都是动作障碍的众所周知的原因，这是化粪池转化的病理生理导管。 AIM 3解决了IPN是否可以钝化感染相关自主功能障碍并中和败血症的危险因素。如果成功，这些实验的数据将直接告知SCI患者有效的非抗生素抗感染策略，以减少与感染相关的死亡率和残疾。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of the Nogo-pathway in experimental spinal cord injury: a meta-analysis of 76 experimental treatments.

DOI：
10.1038/s41598-023-49260-5
发表时间：
2023-12-21
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Hirt, Julian;Khanteymoori, Alireza;Hohenhaus, Marc;Kopp, Marcel A.;Howells, David W.;Schwab, Jan M.;Watzlawick, Ralf
通讯作者：
Watzlawick, Ralf

Bladder Management With Chronic Indwelling Catheter is Associated with Elevated Mortality in Patients with Spinal Cord Injury.

慢性留置导管的膀胱管理与脊髓损伤患者死亡率升高相关。

DOI：
10.1016/j.urology.2022.01.050
发表时间：
2022
期刊：
Urology
影响因子：
2.1
作者：
Baradaran,Nima;Peng,Juan;Palettas,Marilly;Chen,YuYing;DeVivo,MichaelJ;Schwab,JanM
通讯作者：
Schwab,JanM

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

DOI：
10.1212/nxi.0000000000200099
发表时间：
2023-05
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
通讯作者：

Dynamic induction of the myelin-associated growth inhibitor Nogo-A in perilesional plasticity regions after human spinal cord injury.

DOI：
10.1111/bpa.13098
发表时间：
2023-01
期刊：
BRAIN PATHOLOGY
影响因子：
6.4
作者：
Schwaiger, Carmen;Haider, Thomas;Endmayr, Verena;Zrzavy, Tobias;Gruber, Victoria E.;Ricken, Gerda;Simonovska, Anika;Hametner, Simon;Schwab, Jan M.;Hoeftberger, Romana
通讯作者：
Hoeftberger, Romana

A critical reappraisal of corticospinal tract somatotopy and its role in traumatic cervical spinal cord syndromes.

对皮质脊髓束躯体形态及其在创伤性颈脊髓综合征中的作用的批判性重新评估。