Biology subjects

Goodman, M.

Publications and source records attributed to Goodman, M..

3 recordsLinked to original sources

bioRxiv2026

Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy

BackgroundPathogenic variants in PR domain containing 16 (PRDM16) cause pediatric and adult cardiomyopathies characterized by ventricular dilation, systolic dysfunction, and impaired metabolic maturation. Cardiac deficiency of PRDM16 alters metabolic gene expression and long-chain fatty acid (FA) metabolites. However, the downstream mediators involved are not well characterized. Furthermore, whether improving mitochondrial FA metabolism can prevent PRDM16-associated cardiomyopathy is currently unknown. MethodsIn vivo and in vitro approaches using patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse models with Prdm16 deletion/mutation were employed. Transcriptomics and proteomics analyses were conducted, and adeno-associated virus (AAV)-mediated therapy was tested. ResultsHere, we show that a defect in FA metabolism is an early hallmark of PRDM16 cardiac deficiency. We show, for the first time, that PERM1 is a direct downstream target of PRDM16 and is involved in the regulation of FA metabolism through coordinated action with PGC1. Most importantly, neonatal delivery of AAV9-Perm1 in cardiac-specific Prdm16 knockout (Prdm16 cKO) mice markedly improved contractile parameters, reduced left ventricular (LV) dilation, and extended survival. These cardioprotective effects of PERM1 gene therapy occurred independent of restoring FA oxidation. Transcriptional and proteomic analyses of AAV-Perm1-treated Prdm16 cKO mice demonstrated significant improvements in mitochondrial cristae architecture, preservation of sarcomere organization, reduced cardiomyocyte apoptosis, attenuated myocardial fibrosis, and diminished cardiac remodeling. ConclusionsWe identify PERM1 as a direct downstream effector of PRDM16 and uncover a previously unrecognized PRDM16-PGC1-PERM1 axis essential for FA metabolic regulation in the heart. Perm1 gene therapy ameliorated PRDM16-associated cardiomyopathy through post-transcriptional mechanisms involving preservation of mitochondrial and sarcomere integrity. The current study provides preclinical evidence suggesting that Perm1 gene therapy may be a promising therapeutic target to improve the cardiac outcomes of patients affected by pathogenic PRDM16 variants.

physiology↗

bioRxiv2025

EPHB2 promotes diet-induced MASH liver fibrosis

The EphB2 receptor tyrosine kinase is thought to participate in numerous fibroinflammatory disorders. In metabolic dysfunction-associated steatohepatitis (MASH), we find EphB2 becomes strongly overexpressed and overactive in hepatic stellate cells (HSCs) from humans with the disease and from mice fed liver-injuring high fat diets. Genetic deletion of EphB2 or inactivation of its tyrosine kinase catalytic domain suppressed diet-induced MASH fibrosis, while a kinase overactive point mutant displayed exacerbated steatosis and hepatic damage. Silencing EphB2 in primary HSCs dampened the ability of TGF-{beta}/SMAD signals to stimulate the transdifferentiation of stellate cells into profibrotic myofibroblasts, and HSC-specific deletion of the receptor, but not hepatocyte deletion, reduced liver scarring in multiple mouse models, even after fibrosis was established. Finally, a newly developed small molecule tetramerization inhibitor that targets EphB2-Ephrin receptor-ligand interactions effectively blunts inflammation and fibrosis in chemical and diet-induced liver injury models, demonstrating that therapeutically targeting EphB2 can counter MASH fibrosis.

pathology↗

bioRxiv2022

Hippocampal and Medial Prefrontal Cortical Maps Represent Episodes and Rules in a Common Task Space

Memory helps us adapt to changing circumstances but needs guidance to retrieve relevant episodes. Episodic memory requires the hippocampus, the prefrontal cortex (PFC) guides memory retrieval, but how their representations interact is unclear. Using state-space analysis of neuronal spiking, we found CA1 and PFC activity within and between rats formed similar, low-dimensional, region-specific "shapes" representing different tasks tested in the same maze. Task shapes were organized by behaviorally salient variables including time and maze start and goal locations. PFC predicted CA1 representations when both regions were needed to solve a spatial memory task, but not in a cue approach task that required neither region. Task demands imposed common dimensions on CA1 and PFC maps whose topologies distinguished episodic and rule-related computations.

animal behavior and cognition↗