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全球科研项目数据库2026版

Neural Plasticity and Inflammatory Pain

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

OSHINSKY, MICHAEL L.

项目受资助机构

BOSTON CHILDREN'S HOSPITAL

项目编号

5R37NS039518-16

立项年度

2017

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

717563.00美元

学科

Neurosciences; Pain Conditions - Chronic; Pain Research;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

WOOLF, CLIFFORD J

参与机构

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

项目标书摘要：DESCRIPTION (provided by applicant): The overall question to be addressed by this proposal is which immune protein mediators produced during peripheral inflammation contributes to the generation of inflammatory pain by altering ion channel function in nociceptors. To achieve this objective three aims are proposed. In Aim 1 we will first phenotype two models of peripheral inflammation in the adult mouse; a pathogen-based model (intraplantar complete Freund's adjuvant) and a model of sterile tissue injury (surgical incision of the plantar surface of the paw) by examining the temporal pattern of recruitment of different specific immune cells in the two models, to be detected by flow cytometry and Q-RT-PCR, and the time course of the behavioral manifestations of mechanical and thermal hypersensitivity, to be detected by measures of evoked and spontaneous pain-like behavior. We will then determine the relative contribution of different immune cells to the two inflammatory model pain phenotypes using a mixture of mice where a genetic mutation has resulted in loss of a particular immune cell, and validated strategies for depleting specific immune cells. The second specific aim is to use unbiased proteomic and bioinformatics techniques to identify all the immune protein mediators expressed in the two models at the site of inflammation using tryptic digestion, isobaric TMT peptide tagging, fractionation and mass spectrometry. In addition, we will determine which receptors for the induced immune protein mediators are expressed by purified dorsal root ganglion (DRG) neuronal membrane preparations using flow cytometry and biotinylation to label membrane proteins, affinity purification, trypsinization and liquid chromatography/mass spectrometry to identify peptides. The final aim will be test which of the immune protein mediators produced by one or both of the inflammatory models and with a corresponding receptor expressed by DRG neurons activates the JAK- STAT, NFKB, ras/MAPK (ERK and p38), PLC-DAG, IP3 and PI3K signal transduction pathways in DRG neurons or causes calcium influx. We will them perform whole cell patch electrophysiology in current and voltage clamp mode to identify if a candidate immune protein mediator alters excitability, and if so by what changes in TRP and voltage-gated sodium ion channel threshold and kinetics.

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  • 1.Sense and Immunity: Context-Dependent Neuro-Immune Interplay

    • 关键词：
    • allergy and immunology; sensory neurons; asthma; inflammation;neuro-immunological signaling;GENE-RELATED PEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; ALLERGIC AIRWAYINFLAMMATION; INNATE LYMPHOID-CELLS; CAPSAICIN NASAL CHALLENGE;SUBSTANCE-P; DENDRITIC CELL; EOSINOPHIL RECRUITMENT; TYPE-2 IMMUNITY;MAST-CELLS

    The sensory nervous and immune systems, historically considered autonomous, actually work in concert to promote host defense and tissue homeostasis. These systems interact with each other through a common language of cell surface G protein-coupled receptors and receptor tyrosine kinases as well as cytokines, growth factors, and neuropeptides. While this bidirectional communication is adaptive in many settings, helping protect from danger, it can also become maladaptive and contribute to disease pathophysiology. The fundamental logic of how, where, and when sensory neurons and immune cells contribute to either health or disease remains, however, unclear. Our lab and others' have begun to explore how this neuro-immune reciprocal dialog contributes to physiological and pathological immune responses and sensory disorders. The cumulative results collected so far indicate that there is an important role for nociceptors (noxious stimulus detecting sensory neurons) in driving immune responses, but that this is highly context dependent. To illustrate this concept, we present our findings in a model of airway inflammation, in which nociceptors seem to have major involvement in type 2 but not type 1 adaptive immunity.

    ...

  • 2.Breaking barriers to novel analgesic drug development

    • 关键词：
    • MU-OPIOID RECEPTOR; CALCIUM-CHANNEL BLOCKER; II TYPE-2 RECEPTOR; ROOTGANGLION NEURONS; MECHANICAL PAIN HYPERSENSITIVITY; PERIPHERALNERVOUS-SYSTEM; PLACEBO-CONTROLLED TRIAL; CHRONIC CANCER PAIN;NEUROPATHIC PAIN; POTASSIUM CHANNELS

    Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.

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