Biology subjects

Douglas, K.

Publications and source records attributed to Douglas, K..

4 recordsLinked to original sources

bioRxiv2026

A FZD4/LRP5 agonist restores pericyte coverage and vascular integrity by increasing PDGFB signaling

Pericytes, specialized mural cells of capillaries, fulfill crucial physiological functions including promoting endothelial barrier function and regulating angiogenesis. Pericyte loss or dysfunction represents a central pathological feature in diabetic retinopathy (DR) and is increasingly recognized in neurodegenerative diseases as well as in poor stroke outcomes, underscoring an urgent need for therapies that restore pericyte function or promote their regeneration. Here, we utilized a Frizzled4 (FZD4) and Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) agonist antibody (F4L5.13) to investigate the functional consequences of mimicking {beta}-catenin-dependent signaling in CNS endothelial cells (ECs), which is physiologically induced by Norrin or WNT7A/B. In platelet-derived growth factor subunit B (Pdgfb) EC-specific knockout (ECKO) mice, a model of severe developmental pericyte deficiency with secondary blood-retina barrier (BRB) defects and hemorrhages, F4L5.13 significantly promoted retinal pericyte/mural cell proliferation and coverage, improved BRB function, reduced hemorrhages, and normalized vascular morphology. F4L5.13 restored Pdgfb mRNA expression levels from non-recombined cells in Pdgfb ECKO retinas. These findings highlight interactions of {beta}-catenin-dependent signaling and PDGFB production, identify a key pharmacodynamic action of F4L5.13 distinct from anti-VEGF therapies, and suggest that FZD4/LRP5 agonists may have uses as a regenerative pharmacology approach that promotes pericyte coverage in the neurovascular unit.

developmental biology↗

bioRxiv2025

C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function

Macular edema (ME) causes significant vision impairment and occurs in several prevalent retinal diseases including diabetic retinopathy (DR), choroidal neovascularization (CNV), retinal vein occlusion, and uveitis. Retinal edema typically results from dysfunction of the blood-retina barrier (BRB), which is associated with increased retinal expression of complement components. It is unclear whether the classical complement pathway has detrimental or protective roles in the context of BRB dysfunction. Here, we characterize Tspan12 KODBM (Disrupted Barrier Maintenance) mice, a new mouse model of cystoid edema based on genetically and pharmacologically manipulating beta-catenin-dependent norrin/frizzled4 (FZD4) signaling. We assess BRB function, cystoid edema, ERG, and microglia activation outcomes in an aging study with WT, C1qa KO, Tspan12 KODBM, and Tspan12 KODBM; C1qa KO compound mutant mice. Phenotypic analyses and cell-based experiments indicate that C1QA contributes to maintaining basal beta-catenin-dependent signaling and that the absence of C1QA exacerbates BRB dysfunction, cystoid edema, and neuroinflammation in Tspan12 KODBM; C1qa compound mutant mice. Activation of beta-catenin-dependent signaling by a FZD4/LRP5 agonist antibody modality achieves complete resolution of cystoid edema. This study shows that reducing or enhancing norrin/frizzled4 signaling can increase or decrease cystoid edema, respectively, underscoring its potential as a therapeutic target in ME. Furthermore, this study provides novel insights into the contribution of C1QA to BRB maintenance.

neuroscience↗

bioRxiv2024

A neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of Spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the ATAXIN-1 (ATXN1) gene, is characterized by motor dysfunction, cognitive impairment, and death from compromised swallowing and respiration. To delineate specific cell types that contribute to respiratory dysfunction, we utilized the floxed conditional knock-in f-ATXN1146Q/2Q mouse. Whole body plethysmography during spontaneous respiration and respiratory challenge showed that f-ATXN1146Q/2Q mice exhibit a spontaneous respiratory phenotype characterized by elevated respiratory frequency, volumes, and respiratory output. Consequently, the ability of f-ATXN1146Q/2Q mice to increase ventilation during the challenge is impaired. To investigate the role of mutant ATXN1 expression in neural and skeletal muscle lineages, f-ATXN1146Q/2Q mice were bred to Nestin-Cre and Acta1-Cre mice respectively. These analyses revealed that the abnormal spontaneous respiration in f-ATXN1146Q/2Q mice involved two aspects: a behavioral phenotype in which SCA1 mice exhibit increased motor activity during respiratory testing and functional dysregulation of central respiratory control centers. Both aspects of spontaneous respiration were partially ameliorated by removing mutant ATXN1 from neural, but not skeletal muscle, cell lineages.

neuroscience↗

bioRxiv2018

Quantifying platelet margination in diabetic blood flow

Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on the RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a non-monotonic variation with the highest near-wall concentration corresponding to platelets with moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tend to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions, and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.

biophysics↗