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An in vitro study of the mechanisms that underlie changes in neuronal sensitivity and neurite morphology following treatment with microtubule targeting agentsPittman, Sherry Kathleen 11 1900 (has links)
Microtubule targeting agents (MTAs) are chemotherapeutics commonly
used in the treatment of breast, ovarian, lung, and lymphoma cancers. There are
two main classes of MTAs based upon their effects on microtubule stability. The
two classes are the destabilizing agents, which include the drug vincristine, and
the stabilizing agents, which include paclitaxel and epothilone B. These drugs
are highly effective antineoplastics, but their use is often accompanied by several
side effects, one of which is peripheral neuropathy. Peripheral neuropathy can
be characterized by burning pain, tingling, loss of proprioception, or numbness in
the hands and feet. In some patients, the MTA-induced peripheral neuropathy is
debilitating and dose-limiting; however, there are no effective prevention
strategies or treatment options for peripheral neuropathy as the mechanisms
mediating this side effect are unknown. The goal of this work was to investigate
MTA-induced effects on neuronal activity and morphology in order to elucidate
the underlying mechanisms involved in the development of MTA-induced
peripheral neuropathy.
As an indicator of sensory neuronal activity, the basal and
stimulated release of the putative nociceptive peptide, calcitonin gene-related
peptide (CGRP), was measured from sensory neurons in culture after exposure to the MTAs paclitaxel, epothilone B, and vincristine. Neurite length and
branching were also measured in sensory neuronal cultures after treatment with
these MTAs. The results described in this thesis demonstrate that MTAs alter
the stimulated release of CGRP from sensory neurons in differential ways
depending on the MTA agent employed, the CGRP evoking-stimulus used, the
concentration of the MTA agent, the duration of exposure to the MTA agent, and
the presence of NGF. It was also observed that MTA agents decrease neurite
length and branching, independent of the concentration of NGF in the culture
media. Thus, this thesis describes MTA-induced alterations of sensory neuronal
sensitivity and neurite morphology and begins to elucidate the underlying
mechanisms involved in MTA-induced alterations of sensory neurons. These
findings will undoubtedly be used to help elucidate the mechanisms underlying
MTA-induced peripheral neuropathy.
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Sensitivity of airway nociceptor neurons to immune signals in Type 2 inflammation. Sensibilité des neurones nocicepteurs aux signaux immunitaires dans l’inflammation de type 2Crosson, Théo 02 1900 (has links)
Les neurones nocicepteurs jouent un rôle clé dans la défense de l’organisme. Dans le cas des réactions inflammatoires, ils initient des réflexes protecteurs tels que la toux, les vomissements, où les démangeaisons, et participent à la régulation de plusieurs mécanismes physiologiques, notamment la réponse immunitaire. Ils jouent ainsi un rôle prépondérant dans l’inflammation de type 2, souvent associée aux allergies. Mais les mécanismes qui permettent l’activation de ces neurones dans ce contexte sont encore mal connus. Au cours de ce projet de recherche, nous avons exploré la capacité des neurones nocicepteurs à détecter les signaux immunitaires spécifiquement associés à l’asthme. Nous avons ainsi identifié les caractéristiques des nocicepteurs des voies aériennes. Nous avons également démontré leur sensibilité aux allergènes grâce à l’expression du récepteur aux immunoglobulines de type E, FcεR1, ainsi que leur capacité à modifier leur transcriptome en réponse aux cytokines IL-4 et IL-13. Ces travaux soutiennent l’importance de la communication entre systèmes nerveux et immunitaires, et mettent en évidence de nouvelles cibles pour limiter la contribution neuronale aux réactions allergiques. / Nociceptor neurons play a major role in organism defense. In the context of inflammation, they initiate protective reflexes such as cough, vomiting, or itch, and participate in the regulation of various physiological mechanisms, including the immune response. They notably participate in type 2 inflammation, often associated with allergies. But the mechanisms driving the activation of nociceptor neurons in this context are still elusive. During this research project, we investigated the ability of nociceptor neurons to sense immune signals specifically associated with asthma. We identified the characteristics of airway innervating nociceptors. We also demonstrated their sensitivity to allergens through the expression of the Immunoglobulin E receptor FcεR1, as well as their ability to change their transcriptome in response to IL-4 and IL-13. This work supports the importance of bidirectional communication between the nervous and immune systems and unravels new targets to regulate neuronal contribution to inflammation.
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Mechanisms of the downregulation of prostaglandin E₂-activated protein kinase A after chronic exposure to nerve growth factor or prostaglandin E₂Malty, Ramy Refaat Habashy 07 October 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Chronic inflammatory disorders are characterized by an increase in excitability of small diameter sensory neurons located in dorsal root ganglia (DRGs). This sensitization of neurons is a mechanism for chronic inflammatory pain and available therapies have poor efficacy and severe adverse effects when used chronically. Prostaglandin E₂ (PGE₂) is an inflammatory mediator that plays an important role in sensitization by activating G-protein coupled receptors (GPCRs) known as E-series prostaglandin receptors (EPs) coupled to the protein kinase A (PKA) pathway. EPs are known to downregulate upon prolonged exposure to PGE₂ or in chronic inflammation, however, sensitization persists and the mechanism for this is unknown. I hypothesized that persistence of PGE₂-induced hypersensitivity is associated with a switch in signaling caused by prolonged exposure to PGE₂ or the neurotrophin nerve growth factor (NGF), also a crucial inflammatory mediator. DRG cultures grown in the presence or absence of either PGE₂ or NGF were used to study whether re-exposure to the eicosanoid is able to cause sensitization and activate PKA. When cultures were grown in the presence of NGF, PGE₂-induced sensitization was not attenuated by inhibitors of PKA. Activation of PKA by PGE₂ was similar in DRG cultures grown in the presence or absence of NGF when phosphatase inhibitors were added to the lysis and assay buffers, but significantly less in cultures grown in the presence of NGF when phosphatase inhibitors were not added. In DRG cultures exposed to PGE₂ for 12 hours-5 days, sensitization after re-exposure to PGE₂ is maintained and resistant to PKA inhibition. Prolonged exposure to the eicosanoid caused complete loss of PKA activation after PGE₂ re-exposure. This desensitization was homologous, time dependent, reversible, and insurmountable by a higher concentration of PGE₂. Desensitization was attenuated by reduction of expression of G-protein receptor kinase 2 and was not mediated by PKA or protein kinase C. The presented work provides evidence for persistence of sensitization by PGE₂ as well as switch from the signaling pathway mediating this sensitization after long-term exposure to NFG or PGE₂.
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