Biology subjects

Körbelin, J.

Publications and source records attributed to Körbelin, J..

3 recordsLinked to original sources

bioRxiv2025

MiR-23b Neutralization In Brain Endothelium Promotes Blood-Brain Barrier Repair Through Wnt/Beta-catenin Dependent And Independent Mechanisms

Blood-brain barrier (BBB) disruption drives stroke and other CNS disorders pathology, yet restoring its integrity remains challenging. Using an unbiased anti-miR lentiviral screen, miR-23b was identified as a critical negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b using anti-miR-23b, validated by Wnt-reporter, Wnt-rescue, and eCLIP analysis, demonstrates that BEC miR-23b silencing in BECs, enhances junctional protein expression and strengthens barrier function while suppressing transcellular transport. Global multi-omics analysis reveals that miR-23b acts as a robust driver of angiogenesis-specific genes and proteins. Conversely, anti-miR-23b induces the expression of factors essential for BBB stabilization and repair. Notably, anti-miR-23b enhances these protective barrier properties through the multi-faceted regulation of Wnt/{beta}-catenin, TGF-{beta}, Notch, and VEGF signaling mechanisms. Using a 3D microfluidic platform, anti-miR-23b was shown to foster BBB repair by accelerating vessel maturation and enhancing resilience against ischemic injury. Proof-of-concept studies show that BEC specific AAVBR1-anti-miR-23b gene therapy reinforces BBB tight junctions, reduces BBB leakage, and improves outcome measures in a transient middle cerebral artery occlusion (t-MCAO) stroke model. Thus, miR-23b is a critical regulator of cerebrovascular integrity, positioning anti-miR-23b as a promising RNA-based therapy to enhance BBB stability and repair in stroke and other CNS disorders.

neuroscience↗

bioRxiv2021

Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

neuroscience↗

bioRxiv2021

The HDL particle composition determines its anti-tumor activity in pancreatic cancer

Despite significant efforts in the last years to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Late diagnosis and a complex, fibrotic tumor microenvironment produces a therapeutically hardly approachable situation with rapidly emerging resistance mechanisms. In response to this hostile microenvironment, previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis was shown to promote a growth advantage to, and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that efficient, net-cholesterol removal from cancer cells, driven by high-density lipoprotein (HDL) mediated efflux, results in a significant PDAC cell growth reduction, apoptosis and a decreased PDAC tumor development in vivo. This effect is driven by an HDL particle composition-dependent interaction with SR-B1 and ABCA1 on cancer cells, two major lipid flux receptors, which differentially regulate cholesterol transport at the plasma membrane. Eventually, we show that pancreatic cancer patients display reduced plasma levels of HDL-cholesterol, directly translating into a reduced cholesterol efflux capacity of patient-derived plasma samples. We conclude that cholesterol depletion from PDAC cells, together with possible interventions that shunt the import and endogenous synthesis pathways of cholesterol, might represent a promising strategy to increase and complement the currently available treatment options to improve the prognosis of patients suffering from PDAC.

cancer biology↗