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Novel treatments of chronic pain due to repetitive mild traumatic brain injury

重复性轻度创伤性脑损伤引起的慢性疼痛的新疗法

基本信息

批准号：
10754128
负责人：
FLETCHER A WHITE
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-10-01 至 2027-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754128
关键词：
Affect Animals Anxiety Area Astrocytes Basic Science Behavioral Binding Biosensor Brain Brain Concussion CASP1 gene Caspase Categories Cells Central Nervous System Chronic Clinical Sciences Complex Craniocerebral Trauma Cytoplasm Detection Development Diffuse Axonal Injury Elderly Enzyme-Linked Immunosorbent Assay Event Female Functional disorder Generations Head Human IL18 gene Immune System Diseases Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 beta Kinetics Luciferases Maintenance Mediating Mediator Memory impairment Mental Depression Microglia Migraine Minor Modeling Molecular Monitor Multiprotein Complexes Mus Nervous System Neurobiology Neurons Nociception Nucleotides Oligodendroglia Pain Patient-Focused Outcomes Pattern Peptide Hydrolases Pharmaceutical Preparations Play Population Preparation Process Production Protein Region Proteins Rehabilitation therapy Reporter Research Role Signal Transduction Site Specific qualifier value Specificity Stimulus Techniques Testing Therapeutic Time Tissues Transgenic Mice Trauma Veterans Western Blotting axon injury blood-brain barrier crossing brain cell chronic pain chronic pain management chronic widespread pain controlled cortical impact cytokine experimental study falls glial activation immune cell infiltrate improved in vivo in vivo imaging inhibitor injured male mild traumatic brain injury neuroinflammation neuron loss neuropathology novel pain behavior painful neuropathy pharmacologic pre-clinical prevent receptor spatiotemporal therapeutic target therapeutically effective white matter

项目摘要

PROJECT ABSTRACT A frequent condition observed in Veterans and civilian populations is a mild concussive event of the head due to a fall. Frequent falls and associated mild head injuries are a major problem among the older Veterans, especially males and can often lead to impaired memory, depression, anxiety and chronic pain. Numerous studies suggest that the chronic pain state is accompanied by neuroinflammation, though the regional and longitudinal profiles of this trauma-induced process contribution to long-term chronic pain neurobiology are largely unknown. Dysregulation of neuroinflammation following head injury may be modulated by Nod-like receptor protein 3 (NLRP3) inflammasome activation of caspase-1, the cysteine protease that cleaves numerous downstream targets, including pro-IL-1β and pro-IL-18 into their biologically active form. Sustained increase of these cytokines in the central nervous system, in turn, promotes chronic widespread pain that can affects multiple body sites. To better understand the processes which contribute to chronic pain due to a mild concussive event, we will use a transgenic mouse constitutively expressing a luciferase reporter of caspase-1 activation. Utilization of this transgenic mouse in combination with a murine closed-head concussive event is compatible with in vivo imaging and will allow us in the first aim to monitor the spatiotemporal dynamics of a neuroinflammation signaling cascade in the brain of younger and older male and female mice across time. These observations will likely correlate with the onset of chronic pain states. In the second aim, we will determine whether pharmacological inhibition of NLRP3 inflammasome assembly ameliorates chronic neuroinflammation and behavioral correlates of pain in mice. Together, these Aims will provide crucial information on the function of a regulator of neuroinflammation in vivo across time and the degree to which NLRP3 targeting may be a viable therapeutic strategy in head injury- induced chronic pain states.

项目摘要