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TRPM2 overactivation drives hyperlipidemia-induced dysfunction of myeloid cells and neurovascular units.
Get PDFHyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe/ mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2’s pivotal role in medi- ating hyperlipidemia’s detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyper- lipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients
Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients.
Get PDFThe human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity-including financial and time-are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN\u27s collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care
Dynamic single cell transcriptomics defines kidney FGF23/KL bioactivity and novel segment-specific inflammatory targets.
No full textFibroblast growth factor 23 (FGF23) via its coreceptor αKlotho (KL) provides critical control of phosphate metabolism, which is altered in both rare and very common syndromes. However, the spatial-temporal mechanisms dictating kidney FGF23 functions remain poorly understood. Thus, developing approaches to modify specific FGF23-dictated pathways has proven problematic. Herein, wild type mice were injected with rFGF23 for one, four and 12h and kidney FGF23 bioactivity was determined at single cell resolution. Computational analysis identified distinct epithelial, endothelial, stromal, and immune cell clusters, with differential expressional analysis uniquely tracking FGF23 bioactivity at each time point. FGF23 actions were sex independent but critically relied upon constitutive KL expression mapped within proximal tubule (segments S1-S3) and distal convoluted tub/connecting tubule cell sub-populations. Temporal KL-dependent FGF23 responses drove unique and transient cellular identities, including genes in key MAPK-signaling and vitamin D-metabolic pathways via early- (transcription factor AP-1-related) and late-phase (initiation factor EIF2 signaling) transcriptional regulons. Combining ATACseq/RNAseq data from a cell line stably expressing KL with the in vivo scRNAseq pinpointed genomic accessibility changes in MAPK-dependent genes, including the identification of FGF23-dependent early growth factor-1 distal enhancers. Finally, we identified unexpected crosstalk between FGF23-mediated MAPK signaling and pro inflammatory TNF receptor activation via transcription factor NF-κB, which blocked FGF23 bioactivity in vitro and in vivo. Collectively, our findings have uncovered novel pathways at the single cell level that likely influence FGF23-dependent disease mechanisms
A biometric survey of known and prospective murine models of posterior microphthalmia-nanophthalmia.
Get PDFPosterior microphthalmia and nanophthalmia are related genetic conditions that disrupt ocular growth. Here, we conducted a biometric analysis of mouse models to assess shared features of these diseases. Three known microphthalmia alleles (Mfrprd6, Prss56glcr4, and Adipor1tm1Dgen) and two prospective alleles (C1qtnf5tm1.1(KOMP) Vlcg and Prss56em2(IMPC)J) were introgressed onto the C57BL/6J (B6) genetic background and compared to B6 mice at 1 through 12 months of age. Biometric parameters obtained using optical coherence tomography were analyzed statistically to identify strain differences. Fundus imaging and histological analyses were performed to assess ocular morphology. Mfrprd6, Prss56glcr4, and Prss56em2(IMPC)J mice had significantly shorter axial and posterior lengths, and longer anterior chamber depth compared to controls at all ages studied. Adipor1tm1Dgen mice exhibited similar, but less severe, biometric changes. Axial length was not significantly changed in C1qtnf5tm1.1(KOMP)Vlcg mice, but reduced anterior chamber depth and increased lens thickness were observed at one month of age. Lens and corneal thicknesses were otherwise unchanged in the models as compared to B6 controls. Corneal radius of curvature, examined at 4 months of age, was significantly decreased in all models relative to controls. Micropthalmia was observed independent of retinal degeneration (Mfrprd6, Adipor1tm1Dgen) or retinal thickening (Prss56 mutants). Prss56 mutants developed retinal folds that were absent from other mutants and controls. We conclude that, in mice, Mfrp, Prss56, and Adipor1 mutations yield similar microphthalmia phenotypes involving both the anterior and posterior eye. Changes to anterior chamber depth, lens thickness, and corneal curvature in C1qtnf5tm1.1(KOMP)Vlcg mice suggest a role of C1qtnf5 in anterior ocular growth
Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia.
No full textVentricular tachycardia disrupts the heart’s coordinated pump function, leading to sudden cardiac death. Neutrophils, which are recruited in high numbers to the ischemic myocardium, promote these arrhythmias. Comparing neutrophils with macrophages, we found that resistin-like molecule γ (Retnlg or RELMγ) was the most differentially expressed gene in mouse infarcts. RELMγ is part of a pore-forming protein family that defends the host against bacteria by perforating their membranes. In mice with acute infarcts, leukocyte-specific Retnlg deletion reduced ventricular tachycardia. RELMγ elicited membrane defects that allowed cell exclusion dyes to enter the cardiomyocyte interior and also caused delayed afterdepolarizations and later cardiomyocyte death, both of which are strong arrhythmogenic triggers. Human resistin likewise attacked membranes of liposomes and mammalian cells. We describe how misdirected innate immune defense produces membrane leaks and ventricular arrhythmia
Synaptic dysregulation in a mouse model of GRIN2D developmental and epileptic encephalopathy.
No full textGain-of-function (GoF) variants in the GRIN2D gene, encoding the GluN2D subunit of the N-methyl-D-aspartate receptor (NMDAR), cause a severe developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, hypotonia and neurodevelopmental delay. We generated mice carrying the GoF V664I variant, orthologous to V667I, which is present in ∼25% of GRIN2D-DEE patients. Heterozygous mutant mice demonstrate behavioural, neuroanatomical and electrophysiological abnormalities. Lethal convulsive seizures are observed beginning at postnatal Day 17. As adults, heterozygotes display abundant and prolonged runs of spike-wave discharges (SWD) that often persist for minutes. The SWD epochs consist of different populations, differentiated by frequency and association with time-locked behavioural arrest. V664I mutant neurons have enlarged presynaptic terminals and increased synaptic distance. Functional analysis reveals increased inhibitory synaptic activity without changes in NMDAR decay kinetics or presynaptic plasticity in CA1 neurons, and analysis of hippocampal local field potentials shows a 1.5-fold increase in evoked responses and a 1.7-fold increase in action potential generation. Notably, expression of V664I in GABAergic interneurons, but not excitatory forebrain neurons, is sufficient to recapitulate the severe electroclinical phenotype. Altogether, our studies show that altered NMDAR function in inhibitory neurons plays a prominent role in DEE associated with GRIN2D GoF variants, suggesting that targeted genetic treatment may represent a path forward to successful therapeutic intervention
Neurometabolic and vascular dysfunction as an early diagnostic for Alzheimer\u27s disease and related dementias.
No full textINTRODUCTION: Recent studies suggest that the brain undergoes anatomical and functional restructuring, resulting in neurometabolic and vascular dysregulation (MVD) prior to amyloid beta accumulation, which begins at an early age and leads to the onset of Alzheimer\u27s disease (AD).
METHODS: Using a retrospective clinical population (n = 403) from the Alzheimer\u27s Disease Neuroimaging Initiative, cerebral perfusion and metabolism changes across 59 brain regions were evaluated from clinical studies. Results were verified by transcriptomic signatures and clinical cognitive assessments.
RESULTS: Our findings suggest that disease progression follows a stage-dependent MVD pattern that can identify at-risk regions. Although each region progresses at a different pace, regions related to memory, cognition, and motor function showed significant early dysregulation. Importantly, these changes aligned with transcriptomic and cognitive signatures.
DISCUSSION: This study underscores that MVD in brain regions varies by sex and disease stage, making it a sensitive tool for early AD diagnosis. This approach could improve patient monitoring, stratification, and therapeutic testing.
HIGHLIGHTS: The potential of metabolic and vascular dysfunction as an early biomarker was assessed. An analytical method to assess dysregulation via imaging was developed. An analytical and graphical method to visualize the changes across disease spectrum was developed. Brain regions progress at different rates across Alzheimer\u27s disease progression. Results were aligned with transcriptomics and cognitive signatures
Phenotype specific nuclear lamina remodeling in hiPSC derived cardiomyocytes bearing
No full textCardiomyocytes endure physical stress from the myocardium environment while generating their own mechanical strains. The force generated by sarcomeres is transmitted both longitudinally to adjacent sarcomeres and laterally to the cytoskeleton via intermediate filaments. This mechanical stimulus impacts other organelles, including the nucleus, thus playing a vital role in sensing and signaling nuclear adaptations. However, there is limited understanding of how changes in cardiac contractility affect nuclear mechanics. Here, we sought to investigate the effects of hyper- and hypo-contractility in nuclei of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing TNNT2 pathogenic variants associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathies. Transcriptomics analyses of these variant bearing hiPSC-CMs confirmed that differential gene expression occurs and is associated with maladaptive and compensatory responses in HCM and DCM. Our findings show a cause-and-effect link between impaired contractility and nuclear lamina remodeling in cardiomyopathic phenotypes. Disease-induced dysfunctional contractile transients alter the expression of nucleoskeleton protein lamin A/C, influencing nuclear stiffness. These changes in stiffness were rescued by treatment with myosin modulators Mavacamten or Omecamtiv Mecarbil. This study shows that nuclear mechanics is influenced by the interaction between the sarcomere and the cytoskeletal network. Exploring the relationship between contractile dysfunction and nuclear lamina remodeling may reveal new therapeutic targets for cardiomyopathies
Molecular Systems Biology at 20: reflecting on the past, envisioning the future.
No full textAs Molecular Systems Biology marks its 20th anniversary, we take this moment to reflect on two decades of discovery and innovation. Since its launch, the journal has stood at the forefront of integrating quantitative biology, computational modeling, and systems science—helping to shape how we understand complex biological systems