Jennifer Lynn Gibbs - US grants

DESCRIPTION (provided by applicant): Jennifer L. Gibbs, D.D.S., Ph.D. was appointed as an Assistant Adjunct Professor after completing her Endodontic Residency in July 2008. She has prior training in systems neuroscience research including biochemical assays, cell culture, anatomical studies, and behavioral experiments. This K-23 Mentored Patient-Oriented Research Career Development Award will be used to launch her career in translational orofacial pain research with a focus on understanding the mechanisms of neuropathic pain (NP). Research Plan: Dr. Gibbs has propsed a series of studies to evaluate the role of capsaicin-sensitive primary afferent neurons in mediating NP by performing a cross-sectional study on subjects diagnosed with postherpetic neuralgia (PHN) and a complementary series of studies in animals using a model of orofacial NP. In these studies we will determine the relationship between a capsaicin response test (CRT) and outcomes of pain and sensory measures consistent with hyper-responsive primary afferents to determine if the CRT faciliatates a mechanism-based diagnosis of NP. In addition we will test the hjqjothesis that PHN subjects who respond to capsaicin have distinct epidermal and dermal innervation patterns and determine whether histological evaluation of skin biopsies can identify a biomarker for mechanism-based classification of NP. Finally, an animal model will be used to study the contribution of peripheral versus central terminals of capsaicin sensitive primary afferents in the setting of nerve injury Development Plan:Dr. Gibbs will continue her previously initiated work with Dr. Allan Basbaum in his laboratory studying basic mechanisms of pain and relevant techniques including neuroanatomy and pain behavior. In addition Dr. Gibbs will work with Dr. Rowbotham at the UCSF Pain Clinical Research Center to conduct sensory testing studies and collect biopsies from PHN subjects. Dr. Gibbs will continue collaborative efforts with Dr. Schmidt to identify biomarkers for NP and develop a new model of orofacial pain in animals. Dr. Gibbs is also currently pursuing a Master's in Clinical Research to facilitate her ability to perform translational research. Dr. Gibbs has the full support ofher home department and will transition to a tenure track position in July 2009. PUBLIC HEALTH RELEVANCE: These studies will yield novel and important insights into the mechanisms contributing th NP and help define populations (e.g. capsaicin responders) who are more likely to benefit from mechanims targeting analgesic therapies. Neuropathic pain has devastating impact on patients ability to inderact socially, work, and overall enjoyment of life. Improvement in diagnosis of NP is critical for better management of these patients.

DESCRIPTION (provided by applicant): Odontalgia, or toothache, is one of the most common types of pain experienced by both adults and children. The pain can be severe, leading to disruption of daily activities, including missed work, sleep loss, problems eating, and mood alterations. One of the primary mechanisms contributing to odontalgia is inflammation of the dental pulp, or pulpitis. Cold hypersensitivity is one of the hallmarks of pulpitis. Importantly, te molecular mechanisms involved in cold detection in teeth are unknown. Understanding the neurobiology of cold nociception by dental pulp afferents is important for both identifying new strategies for dental pain management and providing insight into the neurobiology of cold nociception. Multiple receptors are potentially involved in the detection and transduction of noxious and non-noxious cold, two of which belong to the transient receptor potential family, the TRPM8 and TRPA1 receptors. This proposal seeks to characterize pulpal afferents, in respect to TRPM8 and TRPA1 expression and function, in order to explicate their role in transducing noxious cold in teeth. Studies in Specific Aim 1A will evaluate TRPM8 and TRPA1 expression and function in the population of trigeminal sensory neurons innervating dental pulp using neuroanatomical methods. Specific Aim 1B will utilize pharmacologic and genetic approaches to evaluate TRPM8 and TRPA1 receptor activity in cells projecting to dental pulp using calcium microfluorometry. Specific Aim 2 will evaluate the contribution of TRPM8 and TRPA1 to activation of central trigeminal nociceptive neurons upon noxious cold stimulation of dental pulp. As TRP receptors have emerged as critically important receptors for nociceptive signaling and integration, understanding their expression and function in pulpal fibers is key to understanding one of the most common types of orofacial pain, odontalgia. Further, these studies will contribute to our understanding of the neurobiology of receptors involved in cold nociception.

Project Summary/Abstract Despite the absolute dependence of the pathology and symptoms of painful pulpitis on bacteria, the mechanisms by which bacteria produce pain in the pulp are not known. In order to identify therapeutic targets to treat painful pulpitis, this project will identify the critical mechanisms mediating LPS-evoked pulpal pain. The long-term goal is to identify novel therapeutic targets to treat painful oral infections. The central hypothesis is that TLR4- TRPA1 receptor interdependent signaling is required for the initial activation of sensory neurons by LPS, while prolonged LPS-evoked pathological neuroplasticity is dependent on TLR4 signaling. This will be tested by completing the following Specific Aims: Aim1 Identify the mechanisms by which LPS initiates symptomatic pulpitis. The hypothesis that LPS causes painful pulpitis by activating sensory neurons through TLR4-initiated signaling that also requires TRPA1 channel activation will be tested. With genetic and pharmacologic approaches, the effects of interfering with TLR4 and TRPA1 receptor signaling on LPS-stimulated nocifensive behaviors and activation of trigeminal sensory neurons will be measured. Further the pathway by which TLR4 activates TRPA1 will be determined. Aim 2 Identify the mechanism by which LPS causes pathological neuroplasticity during pulpitis. The hypothesis that the LPS-mediated neuroplasticity is dependent on TLR4 signaling, and interference with this pathway is needed to reverse established pathological changes in the nervous system. With genetic and pharmacologic approaches the effects of interfering with TLR4 and TRPA1 receptor signaling on LPS-stimulated pathological changes in the trigeminal nucleus (cytokine/chemokine expression, glial upregulation, Fos expression) will be measured. Aim 3 Determine whether neuroinflammatory effects of LPS in human dental pulp are TLR4 or TRPA1 dependent. The hypothesis is that both TRPA1 and TLR4 receptors are required for LPS-evoked CGRP secretion while TLR4 primarily mediates cytokine secretion from human pulp. Using an ex vivo model of human pulp slices the effects of pharmacologic inhibition of TLR4 and TRPA1 on LPS stimulated neurosecretion and cytokine release from pulp will be measured. Upon completion the receptors and signaling pathways mediating LPS evoked pulpal pain will be determined. The scientific contribution provided by these studies is significant because it will identify bacterial specific pain mechanisms, allowing for identification of targets to alleviate symptoms of painful pulpitis while maximally conserving pulp and dental hard tissues. The identification of bacterial-specific pain mechanisms relevant to pulpitis and other painful infections will fundamentally improve health by providing the rationale to pursue precise analgesic therapies.