Biology subjects

Kaczor-Urbanowicz, K. E.

Publications and source records attributed to Kaczor-Urbanowicz, K. E..

3 recordsLinked to original sources

bioRxiv2025

Old World alphaviruses use distinct mechanisms to infect brain microvascular endothelial cells for neuroinvasion

Several alphaviruses bypass the blood-brain barrier (BBB), causing debilitating or fatal encephalitis. Sindbis virus (SINV) has been extensively studied in vivo to understand alphavirus neuropathogenesis; yet the molecular details of neuroinvasion at the BBB remain poorly understood. We investigated alphavirus-BBB interactions by pairing a physiologically relevant, human pluripotent stem cell derived model of brain microvascular endothelial cells (BMECs) with SINV strains of opposite neuroinvasiveness. Our system demonstrates that SINV neuroinvasion correlates with robust infection of the BBB. Specifically, SINV genetic determinants of neuroinvasion enhance viral entry into BMECs. We also identify solute carrier family 2 member 3 (SLC2A3, also named GLUT3) as a potential BMEC-specific entry factor exploited for neuroinvasion. Strikingly, efficient BBB infection is a conserved phenotype that correlates with the neuroinvasive capacity of several Old World alphaviruses, including chikungunya virus. Here, we reveal BBB infection as a shared pathway for alphavirus neuroinvasion that can be targeted for preventing alphavirus-induced encephalitis.

microbiology↗

bioRxiv2024

Silicon Nitride Induces Osteoconduction Via Activated Mitochondrial Oxidative Phosphorylation and Neovascularization

Silicon nitride (Si3N4: SiN) is a thermodynamically stable ceramic material with excellent mechanical properties, and wear and corrosion resistance for industrial applications. SiN has been proposed for orthopedic and dental implant applications owing to its enhanced osteoconduction. However, the biological mechanisms underlying SiN-induced bone formation have not been fully elucidated. In this study, SiN significantly increased in vitro mineralization of human bone marrow mesenchymal stromal cells (BM-MSC) and in vivo peri-implant bone volume in mouse femurs compared to conventionally used titanium (Ti) implants. RNA sequencing of BM-MSC cultured on SiN disks revealed that functional gene clusters associated with mitochondrial oxidative phosphorylation were significantly elevated. SiN in an aqueous solution has been shown to release ammonium/ammonia, which may provide a source for glutamine-dependent energy production, and BM-MSC upregulated the expression of a key enzyme, glutamate-ammonia ligase under osteogenic conditions. Additionally, SiN increased the expression of functional gene clusters involved in vascular formation. The upregulation of HIF1a in vitro and increased VEGFR3-positive blanching vascular structures in vivo implied that SiN induced neovascularization. This study revealed an important mechanism through which SiN stimulated osteoconduction by unique glutamine-driven mitochondrial oxidative phosphorylation and established oxygen and nutrient supply by neovascularization, leading to stable osseointegration.

bioengineering↗

bioRxiv2022

Genetic Architecture of Heart Mitochondrial Proteome influencing Cardiac Hypertrophy

Mitochondria play a key role in the normal function of the heart as well as in the pathogenesis of diseases. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and retrieved 840 mitochondrial proteins (quantified in [≥]50 strains). High-resolution association mapping on their respective abundance levels identified three trans-acting genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Variations of all three were associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. To identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA). DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P = 2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P = 3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P = 6.9E-05). These results indicate that common variations of certain mitochondrial proteins can act in trans to influence mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

genetics↗