Biology subjects

Moore, J. T.

Publications and source records attributed to Moore, J. T..

4 recordsLinked to original sources

bioRxiv2026

Tissue nanotransfection-mediated induction of neurogenic programs promotes myoprotective responses in denervated skeletal muscle

Peripheral nerve injuries often result in prolonged skeletal muscle denervation, leading to progressive atrophy, fibrosis, neuromuscular instability, and loss of regenerative capacity before axons can reinnervate distal targets. Here, we developed a non-viral strategy using tissue nanotransfection (TNT) to deliver the neurogenic transcription factor cocktail Ascl1, Brn2, and Myt1l (ABM) directly to denervated skeletal muscle. In vitro, ABM-transfected myoblasts sustained expression of the reprogramming factors, acquired neuron-like morphologies, upregulated neuronal markers including Tuj1, Map2, and Syp, and exhibited electrophysiological properties consistent with membrane excitability. RNA sequencing confirmed broad activation of neurogenic transcriptional programs, with enrichment of pathways associated with neuronal fate commitment, neuron differentiation, axon guidance, synaptogenesis, and developmental signaling. In a mouse model of sciatic nerve transection, TNT enabled localized ABM expression in denervated gastrocnemius muscle. ABM-TNT treatment accelerated resolution of denervation-associated fibrillation potentials and showed trends toward improved twitch and tetanic torque, compound muscle action potential amplitudes, and muscle mass preservation. Transcriptomic profiling of treated muscles 5 weeks after injury revealed distinct gene expression programs enriched for muscle regeneration, neuromuscular organization, trophic support, extracellular matrix remodeling, angiogenesis, myogenesis, and metabolic adaptation. Network analyses further identified activation of neurogenic regulators, neurotrophic signaling, and vascular-support pathways. These findings establish TNT-mediated ABM delivery as a non-viral platform for inducing neurogenic and myoprotective programs in denervated muscle, suggesting a potential strategy to preserve muscle viability during the prolonged interval required for peripheral nerve regeneration.

bioengineering↗

bioRxiv2025

Developmental and Stress-Induced Effects on 5-HT3R-Expressing Interneurons within Auditory Cortex

Early life stress (ELS) is a well-known predictor of neuropsychiatric disease and contributes to the development of sensory processing deficits that persist throughout life. Organisms are particularly susceptible to the deleterious effects of stress during critical periods, when neuroplasticity is heightened, and initial representations of the sensory environment are mapped to cortex. When ELS is induced during the auditory cortical (ACx) critical period, it impairs both neural and behavioral responses to a variety of auditory stimuli that rely on temporal processing. Mechanisms by which ELS may alter critical period plasticity are of particular interest in understanding ELS-related pathology, including the 5-HT3R interneuron system, which has been implicated in regulating neural activity during critical periods. Here we examined two principal subpopulations of interneurons in primary ACx: VIP and NDNF cells, which account for a majority of cortical neurons expressing 5-HT3R. The expression of the Htr3a gene during normal development and under ELS conditions was quantified using multiplex fluorescent in situ hybridization. We show that densities of cells expressing NDNF and VIP decrease following ear opening and across the ACx critical period, and that ELS results in the maintenance of elevated cell densities compared to age-matched controls. Further, Htr3a in VIP neurons is developmentally upregulated, and its expression is further increased by ELS beyond normal physiologic levels. Stress-induced shifts in these serotonergic interneurons may contribute to deficits that arise in auditory cortical and perceptual responses via effects on local cortical circuitry.

neuroscience↗

bioRxiv2019

Mutational Analysis of an Intrinsically Disordered Region in the E. coli Phosphatase CheZ, a Regulator of Chemotaxis

As a model for Intrinsically Disordered Region (IDR) structure-function, we investigated the IDR present in the E. coli chemotaxis regulatory phosphatase CheZ. The CheZ IDR (amino acids 169-200) is attractive for study because CheZ is part of an exceptionally well characterized and easily tractable system and has an available high-resolution crystal structure. The CheZ IDR contains striking evolutionarily conserved regions that are functionally critical as shown by the fact that changes in single specific amino acids in the conserved IDR regions are able to abolish normal chemotaxis. We have focused on identifying suppressor mutations in the coding region of CheZ G188E, a variant with a >80% reduction in chemotactic swarm activity. Our screen identified 6 suppressor mutations that restored swarm activity to wild-type levels. Interestingly, the suppressor mutations were found not in the CheZ coding region, but in CheY, the phosphoprotein substrate of the CheZ phosphatase. The 6 suppressor mutations were restricted to two amino acid codons. Three suppressor mutations were found at position CheY A42 and three at position CheY M60. A model for how the changes in CheY restore CheZ activity is presented. These studies in dissection of the CheZ IDR will be useful in extending our understanding of IDR structure-function. The accumulating knowledge of IDR principles will be a significant component of a broadening understanding of protein biophysics with direct implications in basic protein structure and protein engineering research.

biochemistry↗

bioRxiv2018

Identification of Kinase Inhibitors that Regulate Nuclear Receptor Nurr1 (NR4A2) Cellular Activity

The ability to regulate the activity NR4A subfamily of nuclear receptors would be potentially useful in the treatment of multiple diseases, but to date, few regulators have been reported. This is likely due to the fact that the NR4A subfamily does not have a typical unoccupied nuclear receptor ligand binding pocket, but rather a pocket that is occupied with hydrophobic side chains of adjacent amino acids. It follows that traditional nuclear receptor assays that seek to identify ligands that bind within the ligand binding pocket would not be successful. We have thus focused on an alternate assay to identify NR4A regulators based on the fact that regulation of NR4A, at least partially, results from phosphorylation/dephosphorylation of the amino terminal region of the protein. We developed a medium throughput cellular assay using a fusion of the amino terminus of Nurr1 (NR4A2) with luciferase reporter and used the assay to screen a large and diverse protein kinase inhibitor set (PKIS). We identified multiple kinase inhibitor compounds from PKIS that significantly increased or decreased the cellular activity of Nurr1. These molecules serve as starting points to discover selective tools for regulation of Nurr1/Nurr1pathway.

pharmacology and toxicology↗