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Reverse Tissue-Manufacturing of the Multicellular Sinoatrial Node Organoids

多细胞窦房结类器官的逆向组织制造

基本信息

批准号：
10660542
负责人：
Sung Jin Park
金额：
$ 61.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660542
关键词：
3-Dimensional Acceleration Address Adenosine Adult Architecture Arrhythmia Atrioventricular Block Biological Assay Biological Pacemakers Calcium Cardiac Cardiac Myocytes Cell Reprogramming Cells Childhood Chronic Clinical Clock protein Connective Tissue Coupled Data Development Disease Engineering Equipment Malfunction Fibroblasts Functional disorder Gene Expression Genetic Transcription Goals HCN4 gene Healthcare Heart Arrest Heart Atrium Heart Block Heart failure Human Hybrids Impairment Implant In Vitro Inferior Longitudinal Studies Mediating Membrane Modeling Myocardial dysfunction Newborn Infant Nodal Operative Surgical Procedures Organoids Pacemakers Pathway interactions Patients Positioning Attribute Preclinical Testing Prevalence Rodent Model Severities Shapes Sinoatrial Node Site Somatic Cell Structure Testing Theoretical model Tissues care burden cell type chronotropic design drug development effective therapy electronic pacemaker heart rhythm implantation improved in silico in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes manufacture millisecond nodal myocyte novel therapeutic intervention optogenetics overexpression pediatric patients prevent programs protein expression public health relevance stem cell differentiation targeted treatment tool

项目摘要

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.

项目总结/文摘