Role of growth hormone and STAT2 in modulating neuroimmune signaling and mast cell recruitment in neonatal inflammatory pain

The National Institute of Allergy and Infectious Diseases awarded Cincinnati Children's Hospital Medical Center $168,296 on October 5, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of growth hormone and STAT2 in modulating neuroimmune signaling and mast cell recruitment in neonatal inflammatory pain.

The research uses nerve-targeted gene knockdown strategies in neonates with carrageenan-induced hind paw muscle inflammation to test the central hypothesis that growth hormone modulates STAT-dependent neuroimmune signaling through PARP14-dependent mechanisms to regulate muscle pain and inflammation. The work includes pain-related behavioral assays and light sheet microscopy to examine how growth hormone influences neuronal sensitization and the release of inflammatory mediators such as monocyte chemoattractant protein 1 and C-X-C motif chemokine ligand 10, which recruit immune cells including macrophages and mast cells to sites of tissue damage.

The project runs through April 5, 2029, with performance at Cincinnati, Ohio. This is a project grant mechanism supporting investigator-initiated research in infectious and allergic diseases. Cincinnati Children's is a tax-exempt nonprofit pediatric hospital and research center that serves as a federal grant recipient, with recent activity concentrated in National Institute of Allergy and Infectious Diseases–funded pediatric clinical research and translational biomedical research.

Abstract

Neonates experience pain as a critical physiological response essential for survival and development. Inflammatory pain in neonates is a complex phenomenon that involves intricate interactions among immune cells, signaling molecules, and sensory neurons. Inflammation triggers a cascade of immune responses aimed at repairing damaged tissues. However, the mechanisms underlying pain modulation in neonates, particularly in the context of inflammation, remain incompletely understood. Our pilot data highlighted growth hormone (GH) as a key regulator of pain responses in neonates following muscle inflammatory injury. GH modulates several signal transducers and activators of transcription (STATS) and upstream modulators of STATS such as poly (ADP-RIBOSE) polymerase 14 (PARP14) in the dorsal root ganglia (DRGS), influencing neuronal sensitization and the release of inflammatory mediators like monocyte chemoattractant protein 1 (MCP1) and C- X-C motif chemokine ligand 10 (CXCL10). These mediators play crucial roles in recruiting immune cells, such as macrophages (MΦS) and mast cells (MCS), to sites of tissue damage, thereby shaping the inflammatory and pain responses. Specifically, neuronal STAT1 knockdown suppressed pain-like behavior and blocked MCP1 expression to prevent MΦS but not MCS infiltration. We do not know whether a similar effect of GH is seen on other STATS, signaling pathways or cytokines within neurons to modulate pain via MCS. Therefore, we will test the central hypothesis that GH modulates stat-dependent neuroimmune signaling through PARP14- dependent mechanisms in neonates to regulate muscle pain and inflammation. We will use nerve-targeted gene knockdown strategies in neonates with carrageenan induced hind PAW muscle inflammation. Pain-related behavioral assays, light sheet microscopy, EX vivo hindpaw muscle/tibial nerve/DRG/spinal cord electrophysiological recording preparations, and molecular analyses (real-time PCR and RNA-SEQ) of peripheral tissues (muscle and DRGS) will be conducted. Aim 1 will elucidate the neuronal pathways downstream of GH that regulate MC-mediated inflammatory pain in neonates. Using a nerve-targeted sirna knockdown strategy, we will test the working hypothesis that knock down of CXCL10 and/or STAT2 within DRG neurons of post-natal day 7 mice with muscle inflammation modulates MC infiltration, neuronal sensitization, gene expression and pain-related behaviors over time (1-3 days post inflammation). Aim 2 will determine the GH- dependent factors within neurons that modulate neuroimmune signaling in neonates following muscle inflammatory pain. Using a similar approach to that described in aim 1, we test the working hypothesis that neuronal PARP14 modulates neonatal inflammation and pain-like behaviors via its regulation of stat expression/function. Results will hopefully lead to new therapies for pediatric inflammatory pain. These studies will also train me in multiple strategies designed to assess neuroimmune signaling and neonatal pain development. The training plan will further develop my skills to become a future independent investigator.