Person: Lee, Seungkyu
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Seungkyu
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Lee, Seungkyu
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Publication Pharmacological Inhibition of Voltage-gated Ca2+ Channels for Chronic Pain Relief(Bentham Science Publishers, 2013) Lee, SeungkyuChronic pain is a major therapeutic problem as the current treatment options are unsatisfactory with low efficacy and deleterious side effects. Voltage-gated Ca2+ channels (VGCCs), which are multi-complex proteins consisting of α1, β, γ, and α2δ subunits, play an important role in pain signaling. These channels are involved in neurogenic inflammation, excitability, and neurotransmitter release in nociceptors. It has been previously shown that N-type VGCCs (Cav2.2) are a major pain target. U.S. FDA approval of three Cav2.2 antagonists, gabapentin, pregabalin, and ziconotide, for chronic pain underlies the importance of this channel subtype. Also, there has been increasing evidence that L-type (Cav1.2) or T-type (Cav3.2) VGCCs may be involved in pain signaling and chronic pain. In order to develop novel pain therapeutics and to understand the role of VGCC subtypes, discovering subtype selective VGCC inhibitors or methods that selectively target the inhibitor into nociceptors would be essential. This review describes the various VGCC subtype inhibitors and the potential of utilizing VGCC subtypes as targets of chronic pain. Development of VGCC subtype inhibitors and targeting them into nociceptors will contribute to a better understanding of the roles of VGCC subtypes in pain at a spinal level as well as development of a novel class of analgesics for chronic pain.Publication Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts(2015) Wainger, Brian; Buttermore, Elizabeth D.; Oliveira, Julia T.; Mellin, Cassidy; Lee, Seungkyu; Saber, Wardiya Afshar; Wang, Amy; Ichida, Justin K.; Chiu, Isaac; Barrett, Lee; Huebner, Eric A.; Bilgin, Canan; Tsujimoto, Naomi; Brenneis, Christian; Kapur, Kush; Rubin, Lee; Eggan, Kevin; Woolf, CliffordReprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. Here, we identify five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons that recapitulate the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibit TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we show that the technique can reveal novel aspects of human disease phenotypes in vitro.Publication A three-dimensional human neural cell culture model of Alzheimer’s disease(Nature Publishing Group, 2014) Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Jennifer; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B.; Zhang, Can; Wainger, Brian; Peitz, Michael; Kovacs, Dora; Woolf, Clifford; Wagner, Steven L.; Tanzi, Rudolph; Kim, Doo YeonAlzheimer’s disease (AD) is the most common form of dementia, characterized by two pathological hallmarks: β-amyloid plaques and neurofibrillary tangles1. The amyloid hypothesis of AD posits that excessive accumulation of β-amyloid peptide (Aβ) leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau2,3. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. AD mouse models with familial AD (FAD) mutations exhibited Aβ-induced synaptic and memory deficits but they were not able to fully recapitulate other key pathological events of AD including clear neurofibrillary tangle pathology4,5. AD patient-derived human neurons showed elevated levels of toxic Aβ species and phosphor-tau (p-tau) but they also could not replicate β-amyloid plaques or neurofibrillary tangles6-11. Here we show that FAD mutations in the amyloid-β precursor protein (APP) and presenilin (PS) 1 genes are able to induce robust extracellular deposition of Aβ, including β-amyloid plaques, in a human neural stem cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of p-tau in the soma and neurites. Immunoelectron microscopy also demonstrated the presence of filamentous tau, only in detergent-resistant fractions from 3D-cultured cells expressing FAD mutations. Inhibition of Aβ generation with β- or γ-secretase inhibitors not only decreased Aβ pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated Aβ-mediated tau phosphorylation. In summary, we have successfully recapitulated Aβ and tau pathology in a single 3D human neural cell culture system for the first time. Our unique strategy for recapitulating AD pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models for other neurodegenerative disorders.Publication Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation(Elsevier BV, 2015) Talbot, Sebastien; Abdulnour, Raja-Elie; Burkett, Patrick; Lee, Seungkyu; Cronin, Shane J.F.; Pascal, Maud A.; Laedermann, Cedric; Foster, Simmie; Tran, Johnathan V.; Lai, Nicole; Chiu, Isaac; Ghasemlou, Nader; DiBiase, Matthew; Roberson, David; Von Hehn, Christian; Agac, Busranour; Haworth, Oliver; Seki, Hiroyuki; Penninger, Josef M.; Kuchroo, Vijay; Bean, Bruce; Levy, Bruce; Woolf, CliffordLung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8+ sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large pore ion channels to specifically block nociceptors, substantially reduced ovalbumin or house dust mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4+ and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma.Publication The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity(Nature Publishing Group UK, 2017) Hohmann, Stephan W.; Angioni, Carlo; Tunaru, Sorin; Lee, Seungkyu; Woolf, Clifford; Offermanns, Stefan; Geisslinger, Gerd; Scholich, Klaus; Sisignano, MarcoChemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.Publication Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity(eLife Sciences Publications, Ltd, 2014) Chiu, Isaac; Barrett, Lee; Williams, Erika; Strochlic, David E.; Lee, Seungkyu; Weyer, Andy D; Lou, Shan; Bryman, Greg; Roberson, David; Ghasemlou, Nader; Piccoli, Cara; Ahat, Ezgi; Wang, Victor; Cobos, Enrique J; Stucky, Cheryl L; Ma, Qiufu; Liberles, Stephen; Woolf, CliffordThe somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4+SNS-Cre/TdTomato+, 2) IB4−SNS-Cre/TdTomato+, and 3) Parv-Cre/TdTomato+ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. DOI: http://dx.doi.org/10.7554/eLife.04660.001Publication Mouse embryonic stem cells can differentiate via multiple paths to the same state(eLife Sciences Publications, Ltd, 2017) Briggs, James; Li, Victor; Lee, Seungkyu; Woolf, Clifford; Klein, Allon; Kirschner, MarcIn embryonic development, cells differentiate through stereotypical sequences of intermediate states to generate particular mature fates. By contrast, driving differentiation by ectopically expressing terminal transcription factors (direct programming) can generate similar fates by alternative routes. How differentiation in direct programming relates to embryonic differentiation is unclear. We applied single-cell RNA sequencing to compare two motor neuron differentiation protocols: a standard protocol approximating the embryonic lineage, and a direct programming method. Both initially undergo similar early neural commitment. Later, the direct programming path diverges into a novel transitional state rather than following the expected embryonic spinal intermediates. The novel state in direct programming has specific and uncharacteristic gene expression. It forms a loop in gene expression space that converges separately onto the same final motor neuron state as the standard path. Despite their different developmental histories, motor neurons from both protocols structurally, functionally, and transcriptionally resemble motor neurons isolated from embryos.