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.

项目摘要/摘要辛迪尔（SA）节点功能障碍的近期患病率，严重程度和医疗保健烧伤强调需要对SA节点功能进行更详细的研究，以便有效治疗和治疗防止SA节点功能障碍。功能障碍的主要机制是起搏器的能力受损细胞诱导赞助节奏（自动性）和电动传导中的不良重塑周围心房组织（SA传导）。但是，当前的SA节点或起搏器模型已经仅限于理论模型和孤立的单细胞类型细胞或细胞簇，留下了一个间隙，以建模自主性心脏收缩，心律以及自动传导中的功能障碍。而且，当前的单细胞型起搏器在一个月的体内整合过程中加剧了心律稳定性，这限制了其作为临床上可行的生物起搏器的应用，能够产生健壮的起搏器和传导。为了解决SA节点模型的当前局限性，该建议旨在开发三维多细胞SA节点器官通过再现人类节点的多细胞组织结构和故障安全机制。与单个细胞类型的生物起搏器相反，人类SA节点是一种天然的器官，精细的绝缘结构和异质细胞组成。而且，人类节点是配备了冗余起搏器站点和传导途径，以保护节奏免受逆境计时刺激。这是受SA节点的结构和故障安全机制的启发，我们旨在增强自动性和SA传导的鲁棒性：首先，我们将专注于增强SA的自动性节点器官通过识别太空人膜和钙时钟蛋白的表达，细胞组成和形状（目标1）。其次，我们将集中精力改善SA节点器官的传导通过协调多个起搏器站点和传导途径（AIM 2）。最后，我们将评估 SA节点器官在体外环境和体内室内室内啮齿动物模型的鲁棒性（AIM 3）。这些研究将定义组织级结构和多细胞组成是否介导了SA节点的鲁棒起搏和传导，可能会揭示高保真组织水平的生物起搏器作为一种新颖 SA节点功能障碍的治疗策略。所提出的类器官适合人类临床前测试主张以加速药物开发，以剖析患者特异性SA节点疾病病理生理学，以及开发可植入的生物起搏器。