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Soluble TNFa in the development of autonomic dysreflexia after spinal cord injury

可溶性 TNFa 在脊髓损伤后自主神经反射异常发展中的作用

基本信息

批准号：
10386794
负责人：
John Roland Bethea
金额：
$ 55.06万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386794
关键词：
Adult Affect Afferent Neurons American Anatomy Attenuated Autonomic Dysreflexia Autonomic nervous system Biological Biological Assay Blood Pressure Blood Vessels Bradycardia Cardiovascular Diseases Cardiovascular system Cells Chest Chronic Complex Data Development Disease Disease susceptibility Electrophysiology (science)Event Flow Cytometry Glutamates Goals Health Heart Rate Hyperactivity Hyperreflexia Hypertension Immune Immune System Diseases Immunosuppression Individual Infection Inflammation Inflammatory Infusion procedures Injury Interneurons Lead Lesion Life Link Mediating Modeling Morbidity - disease rate NF-kappa B NFKB Signaling Pathway Neuroglia Neuroimmune system Neurons Nociception Pathology Peripheral Persons Phase Play Process Prophylactic treatment Public Health Rattus Reaction Reflex action Rodent Role Severities Signal Transduction Spinal Spinal Cord Spinal Cord transection injury Spinal Ganglia Spinal cord injury Spinal cord injury patients Syndrome TNF gene TNFRSF1A gene Telemetry Testing Therapeutic Thoracic spinal cord structure Time Tissues Vascular Diseases base cell type cytokine factor A immune function improved inhibitor injured mature animal mortality neural circuit neuronal excitability prophylactic receptor response sensory stimulus

项目摘要

PROJECT SUMMARY Cardiovascular disease and susceptibility to infection are two leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). One of the major contributors to SCI-associated cardiovascular disease and immune deficiency is the syndrome autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system in response to sensory stimuli below the injury that manifests in 70%-90% of people who have sustained a high SCI. AD is hallmarked by extreme, sudden bouts of hypertension and reflexive bradycardia (i.e. heart rate decrease). Over time, AD events become more severe. These chronic, frequent episodes of hypertension are thought to lead to peripheral vascular dysfunction and immune suppression that contribute to cardiovascular disease and susceptibility to infection, respectively. Merely limiting AD intensity may have significant therapeutic value and improve SCI patients' overall health. The gradual exacerbation of AD is thought to be driven by plasticity of circuits below the lesion that results in an exaggerated spinal sympathetic reflex. Unfortunately, the mechanisms that trigger this maladaptive plasticity are still poorly understood, limiting the development of prophylactic treatments. Interestingly, an activated neuroimmune system is thought to be an underlying factor in aberrant plasticity and hyperexcitable circuits correlated with other pathologies. The pro-inflammatory, soluble form of the cytokine tumor necrosis factor α (sTNFα) has been implicated in initiating inflammation in many contexts. Furthermore, sTNFα is associated with various forms of plasticity that could increase neuronal excitability. We hypothesize that sTNFα in spinal cord below a SCI plays a crucial role in triggering aberrant plasticity that leads to hyperactivity of the spinal sympathetic circuit after SCI and the secondary, intensification phase of AD. Moreover, this proposal will focus on the hypothesis that sTNFa/TNFR1 signaling in neurons involved in the circuit is central to the exacerbation. We will test our hypotheses using an established adult rodent spinal cord thoracic level 3 transection model that reliably results in AD. The overall goals of this multi-PI proposal are to: 1) further interrogate the therapeutic potential of inhibiting sTNFα to reduce AD (Aim 1); 2) investigate the mechanisms underlying how neuronal sTNFα/TNFR1 mediates AD (Aims 2 and 3).

项目总结