Jan. 2024. New NIH R01 with PI (Glukhov) has received the notice of award. Haibo will participate in the project as a Co-investigator (5% effort). Congrats to the team!
Title: Functional Microdomains in the Heart’s Pacemaker: A New Dimension of Cardiac Remodeling
Major goals This project aims to determine the cellular, molecular and electrophysiological mechanisms of mechanical regulation of the sinoatrial node, the primary natural pacemaker of the heart. Our work will define how specialized cardiac cell membrane mechanosensitive domains and associated signaling molecules contribute to both physiological regulation of the sinoatrial node and its remodeling and dysfunction during chronically elevated mechanical overload in hypertension.
Sep. 2023. New NIH R01 with MPI (Eckhardt and Grandi) has been awarded. Haibo will contribute to the project as a Co-investigator (50% effort). Congrats to the team!
Title: Multiomic and Functional Analysis of PVC-Driven Idiopathic VF Predicts New Druggable Targets
In this project, We aim to unravel the mechanistic bases of idiopathic ventricular fibrillation by combining multiomic data, functional phenotyping, and computational modeling, and to use this knowledge to inform new antiarrhythmic strategies.
Aug. 2023. Our most recent paper is online at Cardiovascular Research. Congrats to the team!
Here, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca2+/calmodulin-dependent protein kinase II, CaMKII) involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signaling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive proarrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.
June. 2023. Our most recent collaborative paper with Drs Colas and Ocorr (Sanford Burnham Prebys Medical Discovery Institute, La Jolla) is online at Disease Models & Mechanisms. Congrats to the team!
We integrated a multiplatform modeling of atrial fibrillation by combining 1) human iPSC-derived atrial-like cardiomyocytes, 2) the Drosophila heart model, and 3) computational model of human atria. As proof of concept, we screened 20 AF-associated genes and identified Phospholamban loss of function as a top conserved hit that shortens action potential duration and increases the incidence arrhythmia phenotypes upon stress. Mechanistically, our study reveals that Phospholamban regulates rhythm homeostasis by functionally interacting with L-type calcium channels and NCX. In summary, our study illustrates how a multi-model system approach paves the way for the discovery and molecular delineation of gene regulatory networks controlling atrial rhythm with application to AF.
April. 2023. Haibo and Dr. Bartolucci published a New and Notable article commenting on a latest publication by Drs Moise and Weinberg, who proposed a
novel calcium-feedback control mechanism of the sinoatrial node cells and tissues.
