Zachary Campbell

Research Interests

Pain is pervasive and devastating. Poorly treated chronic pain is the largest source of disability in America with an estimated economic cost of more than 500 billion dollars per year. Moreover, existing strategies to disrupt pain (e.g. opiates) have well known and highly undesirable side effects. Better strategies for preventing chronic pain are desperately needed. In the vast majority of cases, pain originates in the periphery in a specialized type of sensory neuron called a nociceptor. Long-lived changes in their excitability – which are intimately liked to chronic pain – require de novo protein synthesis. Multiple groups have shown that peripheral inhibition of translation diminishes pain associated behaviors in pre-clinical rodent models. This suggests that post-transcriptional regulation of protein synthesis, likely in nerve fibers, is critical for nociceptive plasticity. Our goal is to understand how mRNA control contributes to pain. Our exploration of these mechanisms has led to the identification of new targets for the development of non-opioid analgesics. These are three areas of active investigation (the associated papers were last updated in 2023).

1. mRNA control

We are interested in probing how mRNA biosynthesis, stability, and translation contribute to pain signaling. Despite widespread appreciation for post-transcriptional regulation throughout neurobiology, astonishingly little is known regarding the contributions of these interactions to nociceptive behavioral responses. A major lessor from this work is that RNA-binding proteins feature priminently possibly due to the outsized role of local translation in neuronal plasticity. Here are four relevant publications:

– Iglesias P, Lou TF, Bhat V, Megat S, Burton M, Price T, Campbell ZT. Inhibition of Poly(A)- Binding Protein with an RNA mimic reduces pain sensitization in mice. Nature Communications. 2018. 9(1):10. PMC5750225

– June Bryan de la Peña, Rebecca Chase, Nikesh Kunder, Patrick R Smith, Tzu-Fang Lou, Alexander Stanowick, Prarthana Suresh, Tarjani Shukla, Samuel E Butcher, Theodore Price, Zachary T Campbell. Inhibition of nonsense-mediated decay induces nociceptive sensitization through activation of the integrated stress response. J Neuroscience. 2022. PMID: 36894318

– Kunder N, de la Peña JB, Lou TF, Chase R, Suresh P, Lawson J, Shukla T, Black BJ, Campbell ZT. The RNA-binding protein HuR is integral to the function of nociceptors in mice and humans. J Neuroscience. 2022. 42(49):9129-9141. PMID36270801

– de la Peña JB, Kunder N, Lou TZ, Chase R, Stanowick S, Barragan-Iglesias P, Pancrazio JJ, Campbell ZT. A role for translational regulation by S6 kinase and a downstream target in inflammatory pain. British Journal of Pharmacology. 2021 Dec;178(23):4675-4690. PMC9169231

2. Translational regulation

Protein synthesis is critical for long-lived changes in nociceptive sensitivity. But how do noxious insults trigger preferential patters of translation in sensory neurons? And which products of translation contribute to pain-associated plasticity? We approach these questions using a diverse series of tools that span pharmacology, genetics, and functional genomics. Four relevant publications:

– de la Peña JB, Barragan-Iglesias P, Lou TF, Loerch S, Kunder N, Shukla T, Song J, Megat S, Moy JK, Wanghzou A, Ray PR, Hoyt K, Steward O, Price TJ, Shepherd J, Campbell ZT. Intercellular Arc signaling regulates vasodilation. J Neuroscience. 2021. 15;41(37):7712-7726. PMID: 34326146

– Barragan-Iglesias P, Kunder N, Wanghzou A, Black B, Ray PR, Lou TF, de la Peña JB, Atmaramani R, Shukla T, Pancrazio JJ, Price TJ, Campbell ZT. A peptide encoded within a 5′ untranslated region promotes pain sensitization in mice. Pain. 2021. 162(6):1864-1875. PMC8119312

– Smith PR, Loerch S, Kunder N, Stanowick AD, Lou TF, Campbell ZT. Functionally distinct roles for eEF2K in the control of ribosome availability and p-body abundance. Nature Communications. 2021. 12(1):1-16. PMC8611098

– Barragán-Iglesias P, Kuhn J, Vidal-Cantú GC, Salinas-Abarca AB, Granados-Soto V, Dussor GO, Campbell ZT, Price TJ. Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain. Pain. 2018. 160(1): 160–171. PMC6800106

3.RNA-protein interactions

Recognition of RNA by proteins is the prerequisite for all subsequent regulation. This information can be applied to tailor the specificity of RNA control in human cells and for RNA decoys to probe regulatory mechanisms in vivo. Here are four relevant publications:

– Campbell ZT, Valley CT, Wickens M. A protein-RNA specificity code enables targeted activation of an endogenous human transcript. Nature Struct Mol Biol. 2014. (21): 732-738. PMC4125476

– Zhou Q, Kunder N, De la Paz JA, Lasley AE, Morcos F, and Campbell ZT. Global pairwise RNA interaction landscapes reveal core features of protein recognition. Nature Communications. 2018. 9(1):2511. PMC6023938

– Bhat VD, McCann KL, Wang Y, Fonseca DR, Shukla T, Alexander J, Qiu C, Wickens M, Lo TW, Hall TT, Campbell ZT. Engineering a conserved RNA regulatory protein repurposes its biological function in vivo. eLife. 2019. 8 e43788. PMC6351103

– C Qiu, RN Wine, ZT Campbell, TMT Hall. Bipartite interaction sites differentially modulate RNA-binding affinity of a protein complex essential for germline stem cell self-renewal. Nucleic Acids Research 50 (1), 536-548. PMID34908132