Biology subjects

Kearney, M.

Publications and source records attributed to Kearney, M..

4 recordsLinked to original sources

bioRxiv2026

A critical role for the murine anterior insula in male social avoidance after early life maltreatment.

Maltreatment in children and adolescents poses a major public health crisis as a primary factor for the development of adult psychiatric disorders. However effective treatments for symptoms resulting from early life maltreatment are lacking, in part due to a lack of understanding of how neural circuits are disrupted in adulthood after childhood and adolescent abuse. We used a novel model of developmental maltreatment (early adolescent chronic social defeat stress, eaCSDS) in C57/B6J mice to examine behavioral and circuit-level effects in the adult anterior insula (AI). We combined chemogenetics, whole brain c-fos imaging and multi-site LFP to investigate the role of the AI and related circuitry in adult behavioral dysfunction after early life maltreatment. Behavioral analysis in adult animals reveals that males, but not females, show robust generalized social avoidance after social defeat in early adolescence. Chemogenetic silencing of AI neurons in males, but not females, reduces social avoidance in adulthood after eaCSDS. In males, whole brain c-fos imaging and multi-site LFP recordings further reveal circuit-level disruptions in connectivity to AI, implicating AI dysregulation as a driver of adult male social avoidance after adolescent maltreatment. Together these findings reveal AI as a novel circuits-level target whose activity normalization may reduce fear-based symptoms of adolescent maltreatment in adulthood specifically in males.

neuroscience↗

bioRxiv2026

Integrating Long-Read Structural Variant Analysis with single-nucleus RNA-seq to Elucidate Gene Expression Effects in Disease

Structural variants (SVs) are a major source of genetic diversity, yet how they impact cell types in complex brain diseases remains largely unexplored, partially due to limitations of short-read sequencing. Here, we addressed this fundamental question in Parkinsons disease (PD). generating long-read whole-genome sequencing (WGS) data for 100 post-mortem brain samples from a PD cohort, constructing a high-confidence catalog of 74,552 SVs. To resolve their functional impact, we integrated single-nucleus RNA-sequencing data from two brain regions from the same samples and focused functional analyses on SVs proximal to genes previously nominated as cis-regulated, potential causal targets of PD-associated GWAS loci. Using expression quantitative trait locus and allele-specific expression analyses, we uncovered SVs significantly associated with expression in specific cell types as well as effects shared across cell types. This study demonstrates the power of uniting long-read WGS with transcriptomics to uncover SVs underlying complex disease architecture with cell type resolution.

genomics↗

bioRxiv2021

Paracrine role for endothelial IGF-1 receptor in white adipocyte beiging

There are at least two distinct types of thermogenic adipocyte in mammals: a pre-existing form established during development, termed classical brown adipocytes and an inducible form, beige adipocytes1-3. Various environmental cues can stimulate a process frequently referred to as beiging of white adipose tissue (WAT), leading to enhanced thermogenesis and obesity resistance 4, 5. Whilst beiging of WAT as a therapeutic goal for obesity and obesity-related complications has attracted much attention6-9; therapeutics stimulating beiging without deleterious side-effects remain elusive10. The endothelium lines all blood vessels and is therefore in close proximity to all cells. Many studies support the possibility that the endothelium acts as a paracrine organ11-14. We explored the potential role of endothelial insulin-like growth factor-1 receptor (IGF-1R) as a paracrine modulator of WAT phenotype. Here we show that a reduction in endothelial IGF-1R expression in the presence of nutrient excess leads to white adipocyte beiging, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell autonomous paracrine mechanism. We demonstrate that this is mediated by endothelial release of malonic acid, which we show, using prodrug analogues, has potentially therapeutically-relevant properties in the treatment of metabolic disease.

cell biology↗

bioRxiv2021

IGFBP2 protects against pulmonary fibrosis through inhibiting P21-mediated senescence

Accumulation of senescent cells contributes to age related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) are evolutionarily conserved proteins that play a vital role in many biological processes. Overall, little is known about the functions of IGFBP2 in the epigenetic regulation of cellular senescence and pulmonary fibrosis. Here, we show that Igfbp2 expression was significantly downregulated at both mRNA and protein levels in a low-dose bleomycin-induced pulmonary fibrosis model of aged mice. Using the reduced representation of bisulfite sequencing technique, we demonstrated Igfbp2 downregulation is attributed to DNA methylation of CpG islands in fibrotic lungs of aged mice. Furthermore, Igfbp2 siRNA knockdown increased both P53 and P21 protein levels in mouse lung epithelial cells exposed to hypoxia treatment. Lentiviral mediated expression of Igfb2 decreased P21 protein levels and significantly reduced beta galactosidase activity in mouse lung epithelial cells challenged with a senescent drug (atazanavir) and hypoxia treatments. Using the RT2 Profiler PCR Array, we found that P21, PAI-1, IRF-5 and IRF-7, important regulators of senescence pathway, were significantly downregulated specifically in type-II alveolar epithelial cells (AECs) of aged human-Igfbp2 transgenic mice after bleomycin challenge. Finally, transgenic expression of human-Igfbp2 in type-II AECs from aged bleomycin challenged mice significantly decreased senescent associated secretory phenotype factors and also reduced extracellular matrix markers compared to aged wild-type mice challenged with bleomycin injury. Collectively, these findings reveal that epigenetic repression of Igfbp2 promotes pulmonary fibrosis and that restoring IGFBP2 in fibrotic lungs could prove effective in IPF treatment.

molecular biology↗