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Principal Investigator: Sung Jin Park
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $584,744
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
The recent increasing prevalence, severity, and healthcare burden of sinoatrial (SA) node dysfunction
emphasize the need for more detailed studies of SA node functions that allow for effective therapy to treat and
prevent SA node dysfunction. The major mechanisms of the dysfunction are the impaired ability of pacemaker
cells to induce spontaneous rhythm (automaticity) and adverse remodeling in their electric conduction to
surrounding atrial tissues (SA conduction). However, the current SA node or pacemaker models have been
limited to theoretical models and isolated single cell-type cells or cell clusters, leaving a gap to model the
autonomous cardiac contraction and heart rhythm and dysfunctions in automaticity and SA conduction. Moreover,
the current single cell-type pacemakers worsened heart rhythm stability during one-month in vivo integration,
which limits its application as a clinically viable biological pacemaker capable of generating robust pacemaking
and conduction.
To address the current limitation of SA node models, this proposal aims to develop a three-dimensional
multicellular SA node organoid by reproducing human SA node’s multicellular tissue structure and fail-safe
mechanisms. In contrast to the single cell-type biological pacemakers, human SA node is a natural organoid with
elaborate insulated architecture and heterogeneous cellular composition. Moreover, the human SA node is
equipped with redundant pacemaker sites and conduction pathways to protect the rhythm against adverse
chronotropic stimulations. Thus, inspired by SA node’s structure and fail-safe mechanism, we aim at enhancing
robustness in both automaticity and SA conduction: First, we will focus on enhancing automaticity of SA
node organoids by identifying the expression of pacemaker membrane and calcium clock proteins, cell
composition, and shape (Aim 1). Second, we will concentrate on improving conduction of SA node organoids
by coordinating multiple pacemaker sites and conduction pathways (Aim 2). Last, we will evaluate the
robustness of the SA node organoids in in vitro setting and in vivo atrioventricular block rodent model (Aim 3).
These studies will define if tissue-level architecture and multicellular compositions mediate SA node’s robust
pacemaking and conduction and may reveal a high-fidelity tissue-level biological pacemaker as a novel
therapeutic strategy for SA node dysfunctions. The proposed organoids will be suitable for human preclinical
testing assays to accelerate drug development, for dissecting patient-specific SA node disease pathophysiology,
and for the development of implantable biological pacemakers.
Terms: <0-4 weeks old><21+ years old><3-D><3-Dimensional><3D><Acceleration><Address><Adenosine><Adult><Adult Human><Architecture><Arrhythmia><Assay><Asystole><Atrial><Atrioventricular Block><Bioassay><Biologic Oscillator><Biologic Pacemakers><Biological Assay><Biological Oscillators><Biological Pacemakers><Body Tissues><Calcium><Cardiac><Cardiac Arrest><Cardiac Arrhythmia><Cardiac Atrium><Cardiac Block><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Reprogramming><Cells><Childhood><Chronic><Clinical><Clock protein><Connective Tissue><Coupled><Data><Development><Device Failures><Disease><Disorder><Dysfunction><Endogenous Oscillators><Engineering><Engineering / Architecture><Equipment Malfunction><Fibroblasts><Functional disorder><Gene Expression><Gene Transcription><Genetic Transcription><Goals><HCN4><HCN4 gene><Heart Arrest><Heart Arrhythmias><Heart Atrium><Heart Block><Heart Muscle Cells><Heart failure><Heart myocyte><Human><Hybrids><Hyperpolarization-Activated Cyclic Nucleotide-Gated Potassium Channel 4><Impairment><Implant><In Vitro><Inferior><Longitudinal Studies><Mediating><Membrane><Modeling><Modern Man><Msec><Myocardial depression><Myocardial dysfunction><Newborn Infant><Newborns><Nodal><Operative Procedures><Operative Surgical Procedures><Organoids><Pace Stimulators><Pacemakers><Pathway interactions><Patients><Physiopathology><Position><Positioning Attribute><Preclinical Testing><Prevalence><RNA Expression><Rodent Model><S-A Node><SA node dysfunction><Severities><Shapes><Sick Sinus Syndrome><Sino-Atrial Node><Sinoatrial Node><Sinu-Atrial Node><Sinuatrial Node><Site><Somatic Cell><Structure><Surgical><Surgical Interventions><Surgical Procedure><Testing><Theoretic Models><Theoretical model><Tissues><Transcription><adulthood><atrium><cardiac dysfunction><cardiac failure><cardiac pacemaker cell><cardiac rhythm><cardiomyocyte><cell type><cellular reprogramming><child patients><chronotropic><design><designing><developmental><differentiation of pluripotent stem cells><drug development><effective therapy><effective treatment><electronic pacemaker><healthcare burden><heart dysfunction><heart rhythm><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS cell derived cardiomyocytes><iPSC derived cardiomyocytes><implantation><improved><in silico><in vivo><induced human pluripotent stem cells><induced pluripotent stem cell derived cardiomyocytes><long-term study><longitudinal outcome studies><longterm study><manufacture><membrane structure><millisecond><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><newborn child><newborn children><nodal myocyte><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><optogenetics><overexpress><overexpression><pacemaker cell><pathophysiology><pathway><pediatric><pediatric patients><pluripotent stem cell differentiation><pre-clinical testing><prevent><preventing><programs><protein expression><public health relevance><sinoatrial node dysfunction><sinus node><sinus node dysfunction><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional><tool>