Research Interests:
1) Role of growth factors in peripheral nervous system development. In 1992, in collaboration with Dr. Kathryn Albers, we isolated the first of several lines of mice that overexpressed neuronal growth factors in the skin, a target tissue of sensory neurons that normally express these molecules. We made several important findings from these studies including: 1) Growth factors expression does not redirect sensory fiber targeting (in contrast to sympathetic fibers that are highly chemotropic for growth factor expression). Only the density of peripheral projections was affected by growth factor overexpression. 2) The same growth factor, e.g. NGF, could affect myelinated fibers one way (increasing mechanical responsiveness) and unmyelinated fibers in another (increasing heat sensitivity). 3) Studies in the NGF-overexpressing mice showed that the maturation and pruning of projections to the barrelettes in the trigeminal nucleus (receiving projections from the whiskerpad) was not due to cell death, the canonical theory prior to our studies. 4) Increased expression of NT3, but not NGF or BDNF affected the overlap between peripheral dermatomes. 5) There was significant overlap in the ability of different growth factors to support the same populations of developing neurons. 6) A number of genes critical for nociception and sensory function was shown to be regulated by specific growth factors (e.g., TRPM8 by neurturin, TRPV1 and TRPA1 by NGF and artemin).
Albers KM, Wright DE, Davis BM. (1994) Expression of nerve growth factor in epidermis of transgenic mice causes hyperinnervation of skin and hypertrophy of peripheral nervous system. J. Neurosci. 14:1422-1432.
Stucky CL, Schneider M, Koltzenburg M, Engel MG, Albers KM and Davis BM. (1999) Overexpression of nerve growth factor (NGF) in skin selectively affects the survival, modality and responsiveness of nociceptors. J. Neuroscience. 19:8509-8516.
Malin SA, Christianson JA, Bielefeldt K and Davis BM. (2009) TRPV1 Expression Defines Functionally Distinct Pelvic Colon Afferents. J. Neurosci. 29:743-752.
Wang T, Jing X, DeBerry JJ, Schwartz ES, Molliver DC, Albers KM and Davis BM. (2013) Neurturin overexpression in skin enhances expression of TRPM8 in cutaneous sensory neurons and leads to behavioral sensitivity to cool and menthol. J. Neurosci. 33:2060-2070. PMID: 23365243
2) Role of growth factors in modulating sensitivity sensory neurons innervating the viscera and skin. Our work examining the role of growth factors in development indicated that these molecules were also important in the adult. In particular, we realized that NGF and artemin regulated the expression and function of TRPV1 and TRPA1 and that both of these channels were expressed on visceral afferents, as were the receptors for NGF and artemin. Moreover, we discovered that inflammation, both somatic and visceral, was accompanied by increases in NGF and artemin. In fact, the most rapid and greatest change was in artemin, which prior to our studies, was ignored as a potential driver of inflammatory pain. The pain field has now recognized the potential synergy between these growth factors.
Malin SA, Molliver DC, Koerber HR, Cornett P, Fry R, Albers KM and Davis BM. (2006) GDNF family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J. Neurosci. 26:8588-8599.
Malin SA, Molliver DC, Christianson JA, Schwartz ES, Cornett P, Albers KM and Davis BM. (2011) TRPV1 and TRPA1 function and modulation are target tissue dependent. J. Neurosci. 31:10516-10528.
DeBerry JJ, Schwartz ES and Davis BM. (2014) TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis. Pain 155:1280-1287. PMID: 24704367
DeBerry JJ, Saloman JL, Dragoo BK, Albers KM and Davis BM. (2015) Artemin immunotherapy is effective in preventing and reversing cystitis-induced bladder hyperalgesia via TRPA1 regulation. J Pain, doi: 10.1016/j.jpain.2015.03.014. [Epub ahead of print] PMID: 25892657
3) Functional phenotypic characterization of sensory neurons innervating viscera: esophagus, stomach, colon and bladder. Having employed a novel ex vivo preparation developed by H. Richard Koerber to study cutaneous sensory neurons, we developed preparations that allowed intracellular recordings from either intact vagal or lumbar DRG neurons innervating different portions of the GI tract including esophagus, stomach and colon. These studies found that vagal neurons, which dogma indicated were functionally very different from spinal afferents innervating the visceral responded in a similar manner and in fact, had all of the hallmarks of spinal visceral nociceptors with respect to the roles played by TRP channels and P2X receptors. Our studies of colon afferents found that these neurons were sensitized by neurotrophic factors in a manner that was even more robust that cutaneous afferents.
McIlwrath SL, Davis BM and Bielefeldt K. (2009). Deletion of P2X3 receptors blunts gastro-oesophageal sensation in mice. Neurogastroenterol Motil 21, 890-e866. PMC2837463
Malin SA, Christianson JA, Bielefeldt K and Davis BM. (2009). TPRV1 expression defines functionally distinct pelvic colon afferents. J Neurosci 29, 743-752.PMC2790201
DeBerry JJ, Samineni VK, Copits BA, Sullivan CJ, Vogt SK, Albers KM, Davis BM and Gereau RI. (2018) Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation. Front Integr Neurosci, 2018. 12: p. 5.PMC5816063
Meerschaert KA, Adelman PC, Friedman RL, Albers KM, Koerber HR and Davis BM. (2020) Unique Molecular Characteristics of Visceral Afferents Arising from Different Levels of the Neuraxis: Location of Afferent Somata Predicts Function and Stimulus Detection Modalities. J Neurosci, 2020. 40(38): p. 7216-7228. PMID: 32817244
4) Role of sensory neurons in pancreatic disease and cancer. Because of the expertise available in the GI division at the University of Pittsburgh, special emphasis was placed on studying the role of sensory neurons in pancreatic diseases. With Drs. Fasanella and Christianson (a GI fellow and postdoc fellow, respectively) we phenotyped the sensory afferents innervating the mouse pancreas. This led to a study initiated by Dr. Albers (my primary collaborator) on the role of sensory fiber activity in acute and chronic pancreatitis. These studies demonstrated that neurogenic inflammation was a major driver of disease progression and that both acute and chronic pancreatitis could be slowed or blocked if sensory fibers were silenced with either TRPV1 or TRPA1 antagonists. During these studies, mouse genetic models for pancreatic cancer became available. Because of the link between pancreatitis and pancreatic cancer we began exploring the role of primary afferents in tumorigenesis. Using a genetic mouse model of pancreatic ductal adenocarcinoma (PDAC) we found: 1) that ablation of sensory neurons prior to the tumor formation can halt development of PDAC, 2) that antibodies that block a key sensory neuron growth factors (NGF) can significantly decrease metastasis, but not tumorigenesis, 3) deletions of sensory neurons alters the immune profile in the pancreas and 4) that sensory and other peripheral neurons express immunoregulatory genes that suppress immune function and have the ability to allow developing tumors to escape immunosurveillance.
Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ, Bielefeldt K, Rhim AD, DePinho RA, Albers KM and Davis BM.. (2014) Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74: 1718-17-27. PMID: 24448244
Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA, Rhim AD and Davis BM. (2016). Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. PNAS; 113(11): 3078-3083; PMID: 26929329
Saloman JL, Singhi AD, Hartman DJ, Normolle DP, Albers KM and Davis BM. (2018) Systemic depletion of nerve growth factors inhibits disease progression in a genetically engineered model of Pancreatic Ductal Adenocarcinoma. Pancreas 2018. 47(7):856-863.
Demir IE, Reyes CM, Alrawashdeh W, Ceyhan GO, Deborde S, Friess H, Gorgulu K, Istvanffy R, Jungwirth D, Kuner R, Maryanovich M, Na’ara S, Renders S, Saloman JL, Scheff NN, Steenfadt H, Stupakov P, Thiel V, Verma D, Yilmaz BS, White RA, Wang TC, Wong RJ, Frenette PS, Gil Z and Davis BM. (2020) Clinically Actionable Strategies for Studying Neural Influences in Cancer. Cancer Cell, 38(1): p. 11-14 PMID 32531270
Meerschaert KA, Edwards BS, Epouhe AY, Jefferson B, Friedman R, Babyok OL, Moy JK, Kehinde F, Liu C, Workman CJ, Vignali DAA, Albers KM, Koerber HR, Gold MS, Davis BM, Scheff NN, Saloman JL. Neuronally expressed PDL1, not PD1, suppresses acute nociception (2022b). Brain Behav Immun. 106:233-46. Epub 20220908. doi: 10.1016/j.bbi.2022.09.001. PubMed PMID: 36089217
5) Development of optogenetics to study neuronal-epithelial communications and as a tool to control organ function. In 2012 we began a program to utilize optogenetics to examine intrinsic properties of sensory neurons. We quickly realized that these tools could be used to study how sensory neurons participate in bidirectional communication with their target cells. This concept was the basis of our first publication describing the important role that skin keratinocytes plan in activation of cutaneous afferents. These observations led us to explore the colon epithelium where we found the role of the epithelium to be even more robust than in skin. In reading the relevant literature, we realized that this approach could be used to examine a wide range of important questions regarding the colon epithelium, its role in generating visceral sensations and its contribution to disease symptoms including pain and neurogenic inflammation. At the same time, we also realized that the optogenetic approaches that we were using could be employed to control organ function. This led us to apply to the NIH SPARC program to obtain funds to develop a connectome for the enteric nervous system (OT2 OD023859). For this project, we have been using optogenetics to determine how molecules released by the colon epithelium influence neuronal activity in the myenteric plexus, how extrinsic sensory neurons influence the enteric nervous system and colon motility, and how the sympathetic nervous system coordinates the function of many of the cells (neuronal and non-neuronal) in the colon.
Makadia PA, Najjar SA, Saloman JL, Adelman P, Feng B, Margiotta JF, Albers KM, Davis BM. (2018) Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses. J Neurosci. 2018;38(25):5788-98. PMCID: PMC6010562.
Smith-Edwards KM, Najjar SA, Edwards BS, Howard MJ, Albers KM, Davis BM. (2019) Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice. Gastroenterology. 2019;157(2):522-36 e2. Epub 2019/05/11. doi: 10.1053/j.gastro.2019.04.034. PubMed PMID: 31075226.
Smith-Edwards K. M., B.S. Edwards, C. M. Wright, S. Schneider, K. A. Meerschaert, L. L. Ejoh, S. A. Najjar, M. J. Howard, K. M. Albers, R. O. Heuckeroth and B. M. Davis. (2021) Sympathetic input to multiple cell types in mouse and human colon produces region-specific responses Gastroenterology. 2021 Mar;160(4):1208-1223. PubMed PMID: 32980343
Wright C. M., S. Schneider, K. M. Smith-Edwards, F. Mafra, A. J. L. Leembruggen, M. V. Gonzalez, Deepika R Kothakapa, Jessica B Anderson, Beth A Maguire, Tao Gao, Tricia A Missall, Marthe J Howard, HJoel. C Bornstein, Brian M Davis and Robert O Heuckeroth. (2021) scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3 Cell Mol Gastroenterol Hepatol 2021 (11)\ 1548-1592 e1 PMCID: PMC8099699
Meerschaert, K.A., Davis, B.M., and Smith-Edwards, Insights on Extrinsic Innervation of the Enteric Nervous System and Non-neuronal Cell Types That Influence Colon Function. K.M. (2022a). Adv Exp Med Biol. 1383, 133-139. doi: 10.1007/978-3-031-05843-1_13. PubMed PMID: 36587153