Abdul-Rizaq Hamoud

Protein kinases are central to healthy brain function, regulating critical cellular processes through complex signaling networks. However, understanding differences in kinase signaling of brain cells remains a preeminent challenge of neuroscience. This study aimed to characterize kinase pathways enriched in astrocytes and microglia isolated from male and female murine prefrontal cortex. Using the PamGene PamStation®12 platform, we discovered cell-type-specific kinomic profiles and computationally reconstructed each cell type’s unique active signaling protein-protein interaction network. Notably, our analysis revealed minimal overlap between kinase activity and respective cell-subtype specific kinase transcriptional profiles identified in the Allen Mouse Whole Brain Transcriptomic Cell Type Atlas, highlighting an important limitation of relying solely on gene mRNA expression levels for functional inference in kinase focused studies. These findings also suggest that cell- and sex-specific protein kinase signaling may influence susceptibility to deleterious brain conditions and consequently underscore the importance of considering activity as a biological variable in systems research, offering a new framework for developing targeted therapeutic interventions in precision medicine.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Gene expression alterations in postmortem schizophrenia tissue are well-documented and are influenced by genetic, medication, and epigenetic factors. The Wingless/Integrated (WNT) signaling pathway, critical for cell growth and development, is involved in various cellular processes including neurodevelopment and synaptic plasticity. Despite its importance, WNT signaling remains understudied in schizophrenia, a disorder characterized by metabolic and bioenergetic defects in cortical regions. In this study, we examined the gene expression of 10 key WNT signaling pathway transcripts: IQGAP1, CTNNβ1, GSK3β, FOXO1, LRP6, MGEA5, TCF4, βTRC, PPP1Cβ, and DVL2 in the dorsolateral prefrontal cortex (DLPFC) using postmortem tissue from schizophrenia subjects (n = 20, 10 males, 10 females) compared to age, pH, and postmortem interval (PMI)-matched controls (n = 20, 10 males, 10 females). Employing the R-shiny application Kaleidoscope, we conducted in silico “lookup” studies from published transcriptomic datasets to examine cell- and region-level expression of these WNT genes. In addition, we investigated the impact of antipsychotics on the mRNA expression of the WNT genes of interest in rodent brain transcriptomic datasets. Our findings revealed no significant changes in region-level WNT transcript expression; however, analyses of previously published cell-level datasets indicated alterations in WNT transcript expression and antipsychotic-specific modulation of certain genes. These results suggest that WNT signaling transcripts may be variably expressed at the cellular level and influenced by antipsychotic treatment, providing novel insights into the role of WNT signaling in the pathophysiology of schizophrenia.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration–approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR’s crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.