Biology subjects

Luanpaisanon, P.

Publications and source records attributed to Luanpaisanon, P..

3 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

Inferring the regulation dynamics of oscillatorynetworks from scRNA-seq data

Oscillatory processes such as the cell cycle play critical roles in cell fate determination and disease development. Yet, most current gene regulatory network (GRN) inference methods are based on gene-gene correlations or temporal progression, not adequately accounting for the recurrence in cyclic processes. We hypothesize that constraining the continuous ordering of relative positions along the cell cycle can enhance GRN inference accuracy of cell cycle regulation. To test performance, we evaluated eight representative methods and applied three of them to a mouse retinal progenitor single-cell gene expression dataset [1]. Incorporating cell cycle positions inferred by Tricycle [2] led to significant improvements compared against using experimental times, particularly for early progenitor cells that been hypothesized to be more intrinsically driven by cell cycle regulation. These findings highlight the promise of integrating oscillatory processes into causal inference frameworks to advance our understanding of gene regulation.

bioinformatics↗

bioRxiv2025

Systems analysis reveals neuregulin-1 control of cardiomyocyte size and shape mediated by distinct PI3K and p38 pathways

Pathological and physiological stresses induce diverse forms of cardiac hypertrophy, with distinct manifestations in cardiomyocyte size and shape regulated by still poorly understood signaling networks. Here, we combined high-content morphological profiling, phospho-protein arrays, and systems modeling to characterize the diverse forms of hypertrophy induced by angiotensin II, endothelin-1, insulin growth factor-1, and neuregulin-1. Reverse-phase protein array profiling of neonatal rat cardiomyocytes and partial least squares regression modeling revealed that Akt, GSK3, and MAPK signaling are differentially regulated by hypertrophic agonists and are predictive of distinct phenotypic outcomes. Among these agonists, neuregulin-1 uniquely induced cardiomyocyte elongation in both neonatal rat and human iPSC-derived cardiomyocytes, in addition to increasing cell area. Pharmacological perturbations in neonatal rat cardiomyocytes demonstrated that neuregulin1-induced elongation and area expansion both require PI3K activity, whereas p38 selectively mediates cell area. A logic-based network model incorporating dual-specificity phosphatases were sufficient to capture the amplifying PI3K and transient p38 signaling dynamics driving phenotypic changes. Together, these results identify distinct signaling cascades by which neuregulin-1 coordinates cardiomyocyte size and shape, providing mechanistic insight into how hypertrophic remodeling can be differentially regulated. This systems approach provides new insight into the pathways that drive distinct forms of cardiomyocyte hypertrophy, highlighting opportunities to selectively target maladaptive remodeling in heart failure.

systems biology↗