The problem

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 pain.

Our overaching goal is to understand how mRNAs are controlled in nociceptors. To achieve this, we probe fundamental molecular mechanisms that govern pain-associated plasticity in pre-clinical rodent and human iPSC models. This work has already resulted in the identification of new targets and non-opioid strategies that diminish pain-associated behaviors in roedents. Some of our ongoing studies are described below.

mRNA stability & localization

We are interested in probing how mRNA stability, storage, and localization 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. Relevant publications:

1. 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

2. 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

3. 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

4. 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

Translation

We are interested in understanding how noxious insults alter translation in nociceptors. We have applied ribosome profiling to this problem extensively. This has led to the identification of targets of local translation in nerve fibers, functional upstream open reading frames, and targets implicated in translation that are required for pain-associated behaviors. Relevant publications:

1. 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

2. 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

3. 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

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. Here are four publications that describe our progress on this broadly significant fundamental problem:

1. 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

2. 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

3. 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

4. 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

Physiology

We are interested in the understanding the role of post-transcriptional gene control in the activity of rodent and human sensory neurons. We make extensive use of multi-electrode arrays (MEAs) to understand how RNA control contributes to the function of nociceptors. Relevant publications:

1. Chase R, de la Peña JB, Smith PR, Lawson J, Lou TF, Stanowick AD, Black BJ, Campbell ZT. Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain. FASEB J. 2022 36(7): e22422. PMID35747924

2. Black JB, Atmaramani R, Kumaraju R, Plagens S, Romero-Ortega M, Dussor G, Price TJ, Campbell ZT, Joseph J Pancrazio. Adult mouse sensory neurons on microelectrode arrays exhibit increased spontaneous and stimulus-evoked activity in the presence of interleukin-6. Journal of Neurophysiology. 2018. 120(3): 1374-1385. PMC6171072

3. Rahul R Atmaramani, Bryan J Black, June Bryan de la Peña, Zachary T Campbell, Joseph J Pancrazio. Conserved expression of Nav1. 7 and Nav1. 8 contribute to the spontaneous and thermally evoked excitability in IL-6 and NGF-sensitized adult dorsal root ganglion neurons in vitro. Bioengineering. 2020. 7(22): 1-44. PMID32429423

4. 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

More information

For a detailed overview of translational regulation in pain click here

Examples of our published work can be found here

Papers

The most up to date list of our papers can be found on Pubmed or on our Google scholar page

Selected references

1. 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

2. 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. In press. PMID36270801

3. 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

4.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

Open positions

We are currently recruiting postdocs and graduate students from multiple programs including: MCP, NTP, iPIB, and CMB. To apply, please email the PI a copy of your CV.

Core values

We are a diverse group of scientists that share a passion for discovery. The above image was inspired by posters generated by Sammy Katta (https://sammykatta.com/diversity).

Current lab members

Guadalupe Garcia Perez, PhD CINVESTAV-IPN, Postdoctoral fellow

Pat Smith (right), BS UT-Dallas, Cellular and molecular pharmacology graduate student

Angela Meyer, BS Purdue, iPIB graduate student

Jake Shapiro, BS Colorado College, iPIB graduate student

Sydney O'Flanagan, Genetics undergraduate student, research intern

Zachary Campbell, Associate Professor, Lab head

Alumni

Last known positions - this list spans folks who joined since the founding of the lab in 2015 - updated in early 2023.

Former postdocs

Prof. June Bryan De La Pena - Assistant Professor UNM, Department of Anesthesiology

Prof. Bryan Black (co-mentored with Dr. Joseph Pancrazio) - Assistant Professor UMass-Lowell, Department of Biomedical Engeneering

Prof. Paulino Barregan Iglesias (co-mentored with Dr. Price) - Assistant Professor Universidad Autónoma de Aguascalientes

Dr. Chi Zhang - Assistant Instructor, UT-Southwestern

Former doctoral students

Dr. Rebecca Chase (PhD 2023) - Interviewing for postdocs

Dr. Nikesh Kunder (PhD 2022)- Postdoc MD Anderson, Dr. Jason M. Schenkel

Dr. Vandita Bhat (PhD 2020) - Postdoc NIEHS Stem Cell Biology Group

Former masters students

Prathana Sursh (MS 2022) - PhD student, UT-Dallas

Sanjana Rajeev (MS 2018) - PhD student, USC

Alexa Lasley (MS 2018) - scientist at nanostring

Former staff scientists

Tzu-Fang Lou - Core facility director, UT-Dallas

Jane Song - PhD student, CU-Boulder

Eric Wistrom - PhD student, teaching abroad in Provence

Sam Rovetto - Scientist at Labcorp

Former undergraduates

Lexi Sharkus - RUSCH research intern, summer 2023, applying for graduate programs

Varun Kotipalli - undergraduate student at UT-Dallas

Amber Ho - Pharmacovigilance Specialist

Alex Stanowick - graduate student at UT-Dallas

David Kim - Applying to graduate programs

Krishnateja Kommera - medical student

Siddhardha Maligireddy - postbac NIH intramural researcher NCI

Miloni Joshi - Medical scribe

Emma Henderson - Biomedical engineer at ICA

Ali Abbas - bussiness analyst

Anaid Cándido - Medical Education Quality Officer at National health service UK

Cori Weaver - Operations Manager at Metis Genetics

Dallas Fonseca - Graduate student student University of Minnesota

Sulaiman Syed - Medical Student at University of the Incarnate Word School of Osteopathic Medicine

Abril Ruiz - Clinical Research Associate at Icon

Andrea Kibel - Graduate student University of Notre Dame

Prerana Ramadurgum - DO student UNT Health Science Center

Sanjana Rao - Senior Associate Software Engineer

Neil Mascarenhas - Student at Texas A&M College of Dentistry

Tejesh Guddanti - Medical Student at University of Oklahoma

Contact

You can reach the lab head at this email address: zcampbell /at/ wisc /dot/ edu

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