Jill C. Fehrenbacher, PhD
Associate Professor of Pharmacology & Toxicology
Dr. Fehrenbacher received a B.S. from the University of Southern Indiana in 1999 and a Ph.D. from Indiana University in 2005. She completed her postdoctoral fellowship in the Department of Endodontics at the University of Texas Health Science Center in San Antonio. In 2010, she joined Indiana University as an Assistant Professor with a primary appointment in the Department of Pharmacology and Toxicology and as a member of the Stark Neurosciences Research Institute.
2009: Maria Yeung Dental Research Award, University of Texas Health Science Center at San Antonio, Texas
2008: Dental Science Symposiumn, 1st Place, Postdoctoral Division, University of Texas Health Science Center at San Antonio, Texas
2008: Center for Biomedical Neuroscience Annual Retreat, First Place Postdoctoral Division, University of Texas Health Science Center at San Antonio, Texas
2004 - 2005: K.K. Chen Fellowship, Indiana University School of Medicine, Indianapolis, Indiana
2002: Graduate Student Educational Enhancement Award, Indiana University Graduate School, Indianapolis, Indiana
1995 - 1999: Scholastic Excellence Award, University of Southern Indiana, Evansville, Indiana
1998 - 1999: Bertram Bennett Athletic and Academic Excellence Scholarship, University of Southern Indiana, Evansville, Indiana
Darby LM, Meng H, Fehrenbacher JC (2017). Paclitaxel inhibits the activity and membrane localization of PKCα and PKCβI/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons, Molecular and Cellular Neuroscience, 82: 105.
Shah F, Logsdon D, Messman R, Fehrenbacher JC, Fishel M, Kelley M (2017). Exploiting the APE1-Ref-1 node in cancer signaling and other diseases: from bench to clinic. Nature Partner Journals Precision Oncology, 1: Article #19.
Fehrenbacher JC and Richardson JD (2017). NSAIDs and Acetaminophen. Brody's Human Pharmacology: Mechanism-Based Therapeutics, 6th edition, in press.
Kelley M, Fehrenbacher JC (2017). Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage. Neural Regeneration Research, 12:72.
Malty RH, Hudmon A, Fehrenbacher JC, Vasko MR. (2016) Long-term exposure to PGE2 causes homologous desensitization of receptor-mediated activation of protein kinase A. J Neuroinflammation 11:181.
Pittman SP, Gracias N, Fehrenbacher JC. (2016) Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons. Experimental Neurology, 279:104-115.
Duarte DB, Vasko MR, Fehrenbacher JC (2016). Models of Inflammation: Carrageenan Air Pouch. Current Protocols in Pharmacology, 72:5.6.1-9
Fehrenbacher JC, Bingener J, Aho JM, Wasky PR, Locke EE, Schwesinger WH, Van Sickle KR, Hargreaves KM (2015). Men with acute cholecystitis have higher tissue-based cytokine levels than women: a cross-sectional study. Chirurgia, 28:49-53.
Fehrenbacher JC (2015). Chemotherapy-induced peripheral neuropathy. Prog Mol Biol Tranl Sci: 131:471.
Chen X, Sun W, Glanaris NG, Riley AM, Cummins TR, Fehrenbacher JC, Obukhov AG (2014). Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem: 289: 9600.
Pittman SP, Gracias N, Vasko MR, Fehrenbacher JC (2014). Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture. Experimental Neurology: 253: 146.
Fehrenbacher JC, Vasko MR, Duarte DB (2012). Models of Inflammation: Carrageenan- or Complete Freund’s Adjuvant-Induced Edema and Hypersensitivity in the Rat. Current Protocols in Pharmacology, 5: Unit 5.4.
Duarte DB, Vasko MR, Fehrenbacher JC (2012). Models of Inflammation: Carrageenan Air Pouch. Current Protocols in Pharmacology, 5: Unit 5.6.
Brittain JM, Duarte DB, Wilson SM, Wang Y, Zhu W, Ballard C, Khanna M, Brustovetsky T, Schmutzler BS, Xiong W, Ripsch MS, Ashpole NM, Hudmon A, Meroueh SO, Hingtgen CM, Brustovesky N, Jim X, Vasko MR, Fehrenbacher JC, Hurley JH, White FA, Khanna R. (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nature Medicine; 17:822.
Park KA, Fehrenbacher JC, Thompson EL, Guo CL, Hingtgen CM, Vasko MR. (2010) Nerve Growth Factor Augments Expression of Calcitonin Gene-Related Peptide in Sensory Neurons through activation of the Ras Signaling Cascade. Neuroscience; 171:910.
Fehrenbacher JC, Sun XX, Locke EE, Henry M, Hargreaves KM. (2009) Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue. Pain, 144:253-61.
Fehrenbacher JC, LoVerme J, Clarke W, Hargreaves KM, Piomelli D, Taylor BK. (2009) Rapid Pain Modulation with Nuclear Receptor Ligands. Brain Res Rev, 60:114-24.
Jeske NA, Diogenes A, Ruparel NB, Fehrenbacher JC, Henry M, Akopian AN, Hargreaves KM. (2008) A-kinase anchoring protein mediates TRPV1 thermal hyperalgesia through PKA phosphorylation of TRPV1. Pain, 138: 604-16.
Zhang Y, Fehrenbacher JC, Vasko MR, Nicol GD. (2006) Sphingosine-1-phosphate via activation of a G protein-coupled receptor(s) enhances the excitability of rat sensory neurons. J Neurophys, 96: 1042-52.
Patwardhan AM, Diogenes A, Akopian AN, Berg KA, Clarke WP, Fehrenbacher JC, Hargreaves KM. (2006). PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the Delta opioid receptor. Pain, 125: 114-24.
Fehrenbacher JC, Burkey TH, Nicol GD and Vasko MR. (2005). Tumor necrosis factor alpha and interleukin-1beta stimulate the expression of cyclooxygenase II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root ganglia cells. Pain, 113: 113-22.
Fehrenbacher JC, Taylor CP, Vasko MR. (2003). Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain, 105: 133-41.
Injury, inflammation and a number of diseases and/or drug treatments for diseases can alter the function of sensory neurons in the periphery, spinal cord, and in the brain that result in pain or altered sensation in the periphery. The long-term goal of our research is to understand how diseases and drugs can modulate the function of peripheral sensory neurons to underlie clinical neuronal dysfunction. In addition, we also are interested in how sensory neuron function can alter cancer growth and metastasis. Our research spans a wide scope of science, from systems biology to reductionist studies to examine the function of sensory neurons to single-cell RNAseq studies to identify the effects of diseases and drugs on the transcriptome of individual sensory neurons.
With an increase in survival rates for cancer patients, there is a growing concern regarding the potential of cancer treatments, such as the platinum drugs, microtubule targeted agents (taxanes, vinca alkaloids, and epothilones), proteasome inhibitors and immunomodulators, to produce neurotoxicity, which can significantly impair the quality of life in survivors. Of the various side effects of these agents, chemotherapy-induced peripheral neuropathy (CIPN) is of major concern because it occurs frequently, is debilitating, and is sometimes irreversible. There are currently no treatment options to prevent the development or reverse the symptoms of peripheral neuropathy and this is due, at least in part, to a lack of understanding regarding the molecular mechanisms by which chemotherapeutics alter neuronal function. Therefore, a broad focus of my laboratory has been to discern the mechanisms by which chemotherapeutics alter the sensitivity and morphology of sensory neurons.
Other investigators in the field of CIPN have firmly established paradigms by which treatment of animals with chemotherapeutics results in pain symptoms of neuropathy and intraepidermal nerve fiber (IENF) loss, similar to what is observed in patients in the clinic. However, these animal models provide few opportunities to perform interventional mechanistic studies to elucidate which signaling pathways mediate the effects of chemotherapeutics on neuronal sensitivity and morphology. We started our reductionist studies looking at the effects of the microtubule-stabilizing drug, paclitaxel on sensory neuronal cultures derived from the dorsal root ganglia of rats. We found that inclusion of paclitaxel in the growth medium augmented or reduced the sensitivity of nociceptive sensory neurons that contain the neuropeptide, calcitonin gene-related peptide, dependent upon the concentration of the drug and the duration of exposure. A relatively low concentration of paclitaxel augments transmitter release, whereas a high concentration can reduce transmitter release. Although these reduced studies are limited to examining a direct role of paclitaxel on sensory neurons and mostly discount the involvement of the immune system, in a very simplistic manner they do recapitulate clinical observations. We hypothesized that paclitaxel-induced increases in neuropeptide release could contribute to a ‘gain of function’ of primary sensory neurons, experienced by patients as mechanical allodynia and tingling, whereas the decreased release of neuropeptides could mediate a ‘loss of function’ of primary sensory neurons. A loss of sensory neuron activity could produce numbness and alter the sensitivity to cold temperatures, either through neuronal crosstalk or via disruption of peripheral blood flow in patients, and therefore mediate cold-induced burning pain in patients. We next utilized this in vitro model to examine whether nerve growth factor (NGF), a growth factor that is known to enhance the sensitivity of sensory neurons and promote neurite growth, could protect against the functional and morphological toxicity of paclitaxel and epothilone. We demonstrated that NGF can affect paclitaxel- or epothilone-induced changes in neuropeptide release but has no effect on paclitaxel- or epothilone-induced changes in neurite length, using a high throughput assay to measure neurite length. These are some of the first data available that interrogate whether changes in neuronal sensitivity are causative for the retraction of neurites or vice versa. Our latest manuscript was inspired by the observations that an acute exposure to paclitaxel activated protein kinase C (PKC). Since an acute activation of PKC results in downregulation of the protein, we examined whether a loss of PKC plays a role to maintain the loss of neuronal sensitivity after chronic exposure to paclitaxel, in vitro. Our work indicates that the conventional PKC isozymes are critical mediators that maintain changes in neuronal sensitivity in nociceptive sensory neurons following chronic exposure to paclitaxel. We showed that chronic treatment with paclitaxel inhibits the activity and membrane localization of active PKC to elicit a reduction in the stimulated release of neuropeptide from nociceptive neurons. These findings provide a starting point to mechanistically understand the effects of chronic exposure to paclitaxel on sensory neuronal function.