Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Cell Biology
Total Results:
14196
Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis
BACKGROUND & AIMS/UNASSIGNED:Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy targets both diseases simultaneously, and a roadblock for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females. METHODS/UNASSIGNED:mice (n = 8-13) were fed a western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics, alongside histopathological and biochemical analyses, were integrated to characterize concurrent MASH and atherosclerosis. Transcriptomics was validated in other mouse models and integrated with human data (n = 79). RESULTS/UNASSIGNED:0.04). Lipidomic analyses revealed dysregulated polyunsaturated fatty acid, steryl ester, and dihexosylceramide metabolism. Integration of mouse and human transcriptomes revealed similarities in metabolic and proinflammatory/proatherogenic pathways. CONCLUSION/UNASSIGNED:This sex-based multiomics analysis establishes a murine model of concurrent MASH and atherosclerosis, reveals sex-specific dietary responses, and identifies metabolic and transcriptional pathways with potential utility as biomarkers and therapeutic targets. IMPACT AND IMPLICATIONS/UNASSIGNED:mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectively modeling both diseases in both sexes, while a western diet is effective only in males. Multiomics analyses identified key metabolic and inflammatory pathways linking MASH and atherosclerosis that mirror transcriptomic signatures found in humans, and highlight circulating cholesterol, CCL2, and sphinganine as potential biomarkers. These findings establish a translational model and reveal sex-specific metabolic pathways that will advance our understanding of the shared pathophysiology of MASH and atherosclerosis, and facilitate the development of dual therapeutic approaches, addressing an urgent unmet clinical need.
PMCID:12950431
PMID: 41777553
ISSN: 2589-5559
CID: 6008772
Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis
BACKGROUND & AIMS/UNASSIGNED:Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy targets both diseases simultaneously, and a roadblock for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females. METHODS/UNASSIGNED:mice (n = 8-13) were fed a western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics, alongside histopathological and biochemical analyses, were integrated to characterize concurrent MASH and atherosclerosis. Transcriptomics was validated in other mouse models and integrated with human data (n = 79). RESULTS/UNASSIGNED:0.04). Lipidomic analyses revealed dysregulated polyunsaturated fatty acid, steryl ester, and dihexosylceramide metabolism. Integration of mouse and human transcriptomes revealed similarities in metabolic and proinflammatory/proatherogenic pathways. CONCLUSION/UNASSIGNED:This sex-based multiomics analysis establishes a murine model of concurrent MASH and atherosclerosis, reveals sex-specific dietary responses, and identifies metabolic and transcriptional pathways with potential utility as biomarkers and therapeutic targets. IMPACT AND IMPLICATIONS/UNASSIGNED:mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectively modeling both diseases in both sexes, while a western diet is effective only in males. Multiomics analyses identified key metabolic and inflammatory pathways linking MASH and atherosclerosis that mirror transcriptomic signatures found in humans, and highlight circulating cholesterol, CCL2, and sphinganine as potential biomarkers. These findings establish a translational model and reveal sex-specific metabolic pathways that will advance our understanding of the shared pathophysiology of MASH and atherosclerosis, and facilitate the development of dual therapeutic approaches, addressing an urgent unmet clinical need.
PMCID:12950431
PMID: 41777553
ISSN: 2589-5559
CID: 6008762
Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic cardiomyopathy
BACKGROUND:Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM) with intracellular calcium dysregulation as a major component of its arrhythmia phenotype. Recent adeno-associated viral (AAV) based Pkp2 (AAV-PKP2) gene therapy has shown promising results in a few different PKP2-associated ACM models. Fibroblast growth factor 21 (FGF21) has multiple cardioprotective effects and has recently emerged as a promising therapeutic agent for cardiovascular disease. OBJECTIVES/OBJECTIVE:To assess the efficacy and impact on calcium regulation of a novel AAV8-based FGF21 gene therapy on adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mice. METHODS:Experiments were performed using a PKP2-cKO murine model. AAV8-FGF21 was delivered to adult mice by a single tail vein injection 7 days before tamoxifen-activated PKP2-cKO. Cardiac functions were monitored by echocardiography and electrocardiography. Intracellular calcium transients were investigated in acute isolated adult mouse cardiomyocytes and calcium fluorescent signals were acquired with the IonOptix system. RESULTS:Loss of PKP2 expression caused cardiac mechanical dysfunction and pro-arrhythmic phenotype in adult mouse models. AAV-mediated delivery of FGF21 mitigated the progression of biventricular structural changes, decreased the occurrence of adrenergic arrhythmias, and rescued intracellular calcium imbalance in the setting of PKP2 haploinsufficiency. In contrast, acute in vitro FGF21 treatment for 1 hour had no effect on intracellular calcium transients. CONCLUSIONS:These beneficial effects of AAV8-FGF21 on the PKP2-ACM phenotype suggest a therapeutic landscape for various targeted cardiomyopathies.
PMID: 41759869
ISSN: 1556-3871
CID: 6010612
Majocchi's Granuloma [Case Report]
PMID: 41700678
ISSN: 1533-4406
CID: 6004502
Editorial commentary: The hot phases of arrhythmogenic cardiomyopathy: A burning issue [Editorial]
PMID: 41713668
ISSN: 1873-2615
CID: 6005162
HDL Regulates TGFβ-Receptor Lipid Raft Partitioning, Restoring Contractile Features of Cholesterol-Loaded Vascular Smooth Muscle Cells
Many cells identified as macrophage-like in human and mouse atherosclerotic plaques are thought to be of vascular smooth muscle cell (VSMC) origin. We identified cholesterol-mediated down-regulation of TGFβ signaling in vitro in human (h)VSMCs by localization of TGFβ receptors in membrane lipid rafts, which was reversed by high-density lipoprotein (HDL)-mediated cholesterol efflux. This restored VSMC contractile marker (Acta2) and suppressed macrophage marker (CD68) expression by promoting TGFβ enhancement of Mir145 expression. In vivo, administration of ApoA1 (which forms HDL) to atherosclerotic mice also promoted VSMC Acta2 expression and reduced CD68 expression. Because macrophage-like VSMCs are thought to have adverse properties, our studies not only show mechanistically how cholesterol causes their transition, but also suggest that efflux-competent HDL particles may have a therapeutic role by restoring a more favorable phenotypic state of VSMCs in atherosclerotic plaques.
PMID: 41687341
ISSN: 2452-302x
CID: 6002622
Compressed sensing-based approach identifies modular neural circuitry driving learned pathogen avoidance
An animal's survival hinges on its ability to integrate past information to modify future behavior. The nematode Caenorhabditis elegans adapts its behavior based on prior experiences with pathogen exposure, transitioning from attraction to avoidance of the pathogen. A systematic screen for the neural circuits that integrate the information of previous pathogen exposure to modify behavior has not been feasible because of the lack of tools for neuron type-specific perturbations. We overcame this challenge using methods based on compressed sensing to efficiently determine the roles of individual neuron types in learned avoidance behavior. Our screen revealed that distinct sets of neurons drive exit from lawns of pathogenic bacteria and prevent lawn re-entry. Using calcium imaging of freely behaving animals and optogenetic perturbations, we determined the neural dynamics that regulate one key behavioral transition after infection: stalled re-entry into bacterial lawns. We find that key neuron types govern pathogen lawn-specific stalling but allow the animal to enter nonpathogenic Escherichia coli lawns. Our study shows that learned pathogen avoidance requires coordinated transitions in discrete neural circuits and reveals the modular structure of this complex adaptive behavioral response to infection.
PMID: 41666040
ISSN: 2050-084x
CID: 6001952
Establishing dermatopathology encyclopedia DermpathNet with Artificial Intelligence-Based Workflow
Accessing high-quality, open-access dermatopathology image datasets for learning and cross-referencing is a common challenge for clinicians and trainees. To establish a comprehensive open-access dermatopathology dataset for educational, cross-referencing, and machine-learning purposes, we employed a hybrid workflow to curate and categorize images from the PubMed Central (PMC) repository. We used specific keywords to extract relevant images, and classified them using a novel hybrid method that combined deep learning-based image modality classification with figure caption analyses. Validation on 651 manually annotated images demonstrated the robustness of our workflow, with an F-score of 89.6% for the deep learning approach, 61.0% for the keyword-based retrieval method, and 90.4% for the hybrid approach. We retrieved over 7,772 images across 166 diagnoses and released this fully annotated dataset, reviewed by board-certified dermatopathologists. Using our dataset as a challenging task, we found the current image analysis algorithm from OpenAI inadequate for analyzing dermatopathology images. In conclusion, we have developed a large, peer-reviewed, open-access dermatopathology image dataset, DermpathNet, which features a semi-automated curation workflow.
PMID: 41651886
ISSN: 2052-4463
CID: 6000722
The International Guideline for the Definition, Classification, Diagnosis and Management of Urticaria
This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA2LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
PMID: 41649409
ISSN: 1398-9995
CID: 6000592
A targetable developmental program co-regulates angiogenesis and immune evasion in melanoma
Ultraviolet (UV)-induced DNA mutations generate genetic drivers of cutaneous melanoma and numerous neoantigens that can trigger anti-tumor immunity. Melanoma cells must therefore rapidly evade immune detection by modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Although angiogenesis typically facilitates immune infiltration, solid tumors increase vascularization while limiting immune cell entry. By comparing transcription factor (TF) expression across early-stage melanoma, naevi, and other cancers, we found that the homeodomain TF HOXD13 drives a melanoblast-like program upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we show that HOXD13 promotes tumor growth by enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D enhancer-promoter contacts activating VEGFA, SEMA3A, and CD73, which remodel vasculature and elevate immunosuppressive adenosine. Consistently, HOXD13-induced tumor growth is reversed by combined VEGFR and adenosine receptor (AdR) inhibition, revealing a dual pro-angiogenic and immunosuppressive HOXD13 axis with therapeutic relevance.
PMID: 41631877
ISSN: 2159-8290
CID: 5999692
