Biology subjects

Bradley, L. A.

Publications and source records attributed to Bradley, L. A..

4 recordsLinked to original sources

bioRxiv2026

Therapeutic targeting of MYBPC3 mutation-specific hypertrophic cardiomyopathy guided by network modeling

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death with genotype positive cases most commonly associated with mutations of cardiac myosin binding protein-C (MYBPC3). Recently approved drugs for HCM target the myofilaments rather than the aberrant molecular signaling pathways that drive long-term remodeling. Here, we identified a patient with familial HCM that was associated with a MYBPC3 W1078 truncation mutation. A CRISPR knock-in mouse model of the orthologous mutation MYBPC3 W1082 exhibited marked cardiac hypertrophy including wall thickening, reduced ejection fraction, and decreased survival. To identify pathways, mechanisms, and potential candidate therapeutics, we integrated the MYBPC3 mutation into a computational network model of the signaling underlying familial cardiomyopathy. The network model predicted that the MYBPC3 mutation drove hypertrophy through mTOR/PI3K pathways, consistent with the results of RNA sequencing of cardiomyocytes of MYBPC3W1082*/W1082* mice. A virtual drug screen using FDA-approved drugs predicted that the mTOR inhibitor, Rapamycin, could mitigate mutation-induced hypertrophy. We then experimentally validated the effects of Rapamycin on hypertrophic responses using cultured cardiomyocytes. Further, Rapamycin attenuated cardiac hypertrophy and fibrosis of MYBPC3W1082*/W1082* mice in vivo. mTOR inhibitors (rapamycin and everolimus) were associated with a decreased incidence of cardiac hypertrophy associated diagnostic codes in patients in the FDA Adverse Events Reporting System. Query of electronic health records and echocardiograms from a University of Virginia cohort of patients treated with mTOR or calcineurin inhibitors showed that patients prescribed everolimus or tacrolimus had reduced LV wall thicknesses. Together, these studies suggest that targeting mTOR as a translationally relevant target for a mutation-induced hypertrophic cardiomyopathy, as well as demonstrating the utility of guiding precision therapies by iterating between network models and experimental validation.

physiology↗

bioRxiv2025

Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury

The adult mammalian heart has a limited ability to regenerate lost myocardium following myocardial infarction (MI), largely due to the poor proliferative capacity of cardiomyocytes (CMs). Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a known regulator of cell quiescence, though the mechanisms underlying its function remain unclear. Previous studies have shown that pharmacological inhibition of DYRK1A using harmine induces CM cell cycle re-entry after ischemia/reperfusion (I/R) MI. Here, we developed a computational network model of DYRK1A-mediated regulation of the cell cycle, which predicts how DYRK1A inhibition promotes CM re-entry. To validate these predictions, we tested selective DYRK1A inhibitors and observed robust induction of cell cycle activity in neonatal rat cardiomyocytes (NRCMs). Integrating our network model with bulk RNA-sequencing data from DYRK1A inhibitor-treated NRCMs, we identified E2F1 as a key transcriptional driver of cell cycle gene expression. Finally, we demonstrate that both pharmacological and post-developmental inhibition of DYRK1A enhances heart function and increases CM cycling following I/R MI. Our findings suggest that functional recovery induced by small molecule inhibitor of DYRK1A is mediated by the induction of cycling CMs. One Sentence SummaryInhibition of DYRK1A through LCTB-92 induces cardiomyocyte cycling and improved heart function in a mouse model of ischemic/reperfusion injury.

pharmacology and toxicology↗

bioRxiv2025

Functional Dissociation in the Developing Superior Temporal Lobe: Language and Theory of Mind

Language and theory of mind (ToM; the ability to infer others mental states) are both crucial for human communication and yet their developmental origins are unclear. Are their neural substrates distinct within the superior temporal lobe (STL) but with opposing lateralization, as in adults? Or do they emerge from common neural substrates during development, perhaps in homologous regions originally involved in more basic social processing? Here we investigate the development of this functional dissociation, and the dissociation of their underlying connectivity fingerprints in a large cohort of children (ages 4-9 years, n=58 sessions) and adults (n=29). We demonstrate for the first time that children show distinct patterns of neural specificity for language and ToM in STL, just like adults. Children show no evidence of developmental disentangling cross-sectionally or longitudinally. Finally, childrens connectivity fingerprints predicting future language or ToM activation are almost identical to concurrent fingerprints and are largely non-overlapping across domains. While linguistic and ToM processing undergo continued neural specialization to reach the mature adult-like state, they are distinct remarkably early in human development. Our results challenge the idea that language develops from neural processors common for social communication and instead support distinct neural origins of these mental domains.

neuroscience↗

bioRxiv2020

Ablation of endogenously cycling adult cardiomyocytes worsens myocardial function after injury

RationaleEndogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle. ObjectiveWe created and validated a new transgenic mouse, MHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted DKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), DKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI. Methods and ResultsA tandem DKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The DKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, DKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre- treated DKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 {+/-} 0.5 vs. 3.3 {+/-} 0.3 CMs per ten-micron section, N = 8 mice, n = 16 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was [~]9 to 1 (5.2 {+/-} 0.4 single vs. 0.6 {+/-} 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in DKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls. ConclusionsAlthough scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

cell biology↗