2017 — 2021 |
Ruparel, Shivani B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Peripheral Brain-Derived Neurotrophic Factor (Bdnf) Signaling in Oral Cancer Pain @ University of Texas Hlth Science Center
Project Summary Numerous studies have indicated that pain is the top ranked symptom in head and neck cancer (HNC) patients. However, available treatments are limited and associated with severe side effects adding substantially to the burden of having cancer. Thus, there is a critical need for novel analgesics. However, there is a large gap in knowledge for oral cancer pain mechanisms and thus pain control is often incomplete. Because pain in oral cancer occurs even before a tumor becomes clinically apparent, this cardinal symptom indicates that cancer cells control the activities of surrounding nociceptors at the site of the tumor. The objective here is to study a novel mechanism for oral cancer pain by which tumor cells interact with sensory neurons at the orthotopic site. Our central hypothesis is that Brain-derived neurotrophic factor (BDNF) is released from oral squamous cell carcinoma (OSCC) cells and activates adjacent sensory fibers, contributing to OSCC-induced pain. This hypothesis is based on compelling preliminary data demonstrating that BDNF levels are elevated in oral tumor in mice and that antagonizing the BDNF receptor reverses pain-like behaviors in vivo. We will employ behavioral, biochemical, anatomical methods as well as electrophysiological analysis of lingual nerve fibers that allows studying tumor-nerve interactions in situ, to study the aims: Aim 1: Determine whether OSCC-released BDNF contributes to oral cancer pain. Using superfusion techniques, electrophysiology and behavioral assays, this aim will determine the release of BDNF from tongue tumor as well as test whether released BDNF regulate surrounding nerve fibers activities in the tongue and produce pain-like behaviors in vivo. Results from male and female mice will be compared to determine BDNF- induced sexually dimorphic effects. Aim 2: Determine whether TrkB and p75 receptors (p75R) play a role in BDNF mediated peripheral oral cancer pain. The effects of pharmacological and molecular inhibition on the TrkB and p75 receptors in sensory neurons will be determined with electrophysiologic recordings. Follow-up experiments will test the effect of application of recombinant human BDNF on sensory fiber activities in naïve animals. Sex-dependent differences will also be determined. Aim 3: Determine downstream BDNF signaling pathways in mediating oral cancer pain. Using male and female mice, this aim will employ anatomical and electrophysiological methods to identify the downstream pathways of TrkB and the p75 receptor that may play a role in BDNF-induced oral cancer pain. Collectively, experiments proposed herein provide critical and comprehensive tests of the central hypothesis. The translational significance of this project is strengthened by the use of human cancer cells and a clinically relevant orthotopic model that mimics patient symptoms as well as the novel electrophysiology method to study tumor-nerve interaction at the very site of tumor development. RELEVANCE: It is often very difficult to treat pain from oral cancer with available medications due to limited effectiveness or rapid development of tolerance. We propose a highly novel mechanism that will evaluate the peripheral role of BDNF signaling in oral cancer pain. The research project addresses a significant medical problem with an innovative hypothesis and newly developed experimental methods. Moreover, there is a strong rationale for the focus of this application, as BDNF signaling is known to trigger pain and contribute to tumor progression and chemoresistance in head and neck cancer.
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0.947 |
2019 — 2021 |
Akopian, Armen N [⬀] Ruparel, Shivani B Tumanov, Alexei V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Light and Lymphotoxin Targeting For the Treatment of Chronic Orofacial Pain Conditions @ University of Texas Hlth Science Center
Orofacial chronic pain mismanagement substantially contributes to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat this problem, it is necessary to elucidate a critical gap in knowledge by identifying and vigorously validating novel therapeutic targets controlling the development and maintenance of chronic orofacial pain. The current paradigm implies that orofacial conditions, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, could trigger maladaptation of the immune system and cell plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, are critical components controlling a delicate balance between protective immunity and immunopathology during chronic inflammatory diseases. The objectives of this proposal are: first, to rigorously validate whether local blockade of LIGHT and LT? signaling via LT? receptor (LT?R) or Herpes Virus Entry Mediator (HVEM; TNFRSF14) prevent the development and/or inhibit maintenance of chronic pain in several models of TMJD and oral cancer; and second, to identify LIGHT and LT? signaling-induced plasticity of immune, stromal and tumor cells in masseter muscle and tongue, as well as of sensory neurons in trigeminal ganglia (TG), leading to orofacial chronic pain. Based on the existing literature and our preliminary data, our central hypothesis is that targeting LIGHT and LT? signaling will prevent the development and inhibit maintenance of chronic pain produced by TMJD and oral cancer via peripheral mechanisms involving plasticity of immune, stromal and tumor cells as well as sensory neurons. Our hypothesis will be tested by three relevant yet independent aims. Aim 1 validates whether local LIGHT and LT? inhibition in masseter muscle prevents the development and blocks maintenance of chronic pain in TMJD models. Aim 2 defines contribution of LIGHT and LT? to immune, stromal and neuronal cell plasticity during TMJD. Aim 3 determines whether LIGHT and LT? signaling contribute to the development and maintenance of chronic pain in oral cancer models via regulation of cell plasticity in tongue. The proposed study is innovative because it validates novel targets to facilitate the development of orofacial chronic pain therapeutics; and proposes conceptually novel peripheral regulatory mechanisms involving LIGHT and LT? signaling that control the development and maintenance of TMJD and oral cancer chronic pain. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain; and offers targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.
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0.947 |
2020 |
Akopian, Armen N [⬀] Ruparel, Shivani B Tumanov, Alexei V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Light and Lymphotoxin Induced Modulation of Trigeminal Ganglia Sensory Neuron Excitability @ University of Texas Hlth Science Center
Mismanagement of chronic orofacial pain substantially contributes to opioid misuse and opioid related deaths as well as to cardiovascular, renal and neurological complications at epidemic proportions. There is a critical gap in knowledge about the management of chronic orofacial pain which can be addressed by identifying and vigorously validating novel therapeutic targets controlling its development and maintenance. We have identified such targets - LIGHT and Lymphotoxin-beta (LT?), and have been awarded a R01 DE029187 grant within the HEAL Initiative program FOA RFA-NS-18-043 (title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment) to vigorously validate these novel therapeutic targets in control of development and maintenance of chronic orofacial pain. This parent grant aims to test central hypothesis that targeting LIGHT and LT? signaling prevents the development of and inhibits maintenance of chronic pain produced by temporomandibular muscle and joint disorders (TMJD) and oral cancer via peripheral mechanisms involving plasticity of immune, stromal and tumor cells as well as sensory neurons. The objectives of this current proposal, which is submitted in response to opportunity ?Research Supplement to Promote Diversity in Health-Related Research (PA-20-222)?, are: first, to promote diversity in health-related research by training Ms. Karen Lindquist, a PhD student from a background underrepresented in bio-medical sciences, and second, to enhance a basic science aspect of the parent application by testing the central hypothesis that LIGHT and LT? modulate TMJD-induced excitability of specific populations of sensory neurons innervating the masseter muscle and the TMJ. Our hypothesis will be tested by two related yet independent aims. Aim 1 identifies and characterizes sensory neuron types innervating the masseter muscle and the TMJ in naïve mice. Aim 2 defines the contribution of LIGHT and LT? to TMJD-induced excitability of different groups of trigeminal sensory neurons innervating the masseter muscle and the TMJ. The proposed study will promote diversity in health-related research, since a PhD student from a background underrepresented in bio-medical sciences will be one of main beneficiaries of this study. This study provides an outstanding training opportunity, since it contains almost all aspects of a multi-level research training program, including a multi-disciplinary approach to research, data analysis and correlation to the literature, presentation and publication of research findings, development of research collaborations and project management. It is highly innovative and significant because it will generate fundamental data on sensory neuron type-dependency from target tissues in the trigeminal system. The proposal also advances our understanding of the mechanisms regulating excitability of different sensory neuron types by LIGHT and LT?.
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0.947 |