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.

项目概要/摘要最近窦房结功能障碍的患病率、严重程度和医疗负担不断增加强调需要对窦房结功能进行更详细的研究，以便采取有效的治疗方法预防SA结功能障碍的主要机制是起搏器能力受损。细胞诱导自发节律（自动性）和电传导的不良重塑周围心房组织（SA传导）然而，目前的SA结或起搏器模型已被证实。仅限于理论模型和孤立的单细胞类型细胞或细胞簇，留下了建模的空白自主性心脏收缩和心律以及自主性和 SA 传导功能障碍。目前的单细胞型起搏器在一个月的体内整合过程中心律稳定性恶化，这限制了其作为能够产生强大起搏作用的临床上可行的生物起搏器的应用和传导。为了解决当前 SA 节点模型的局限性，该提案旨在开发一个三维多细胞 SA 结类器官，通过复制人类 SA 结的多细胞组织结构和故障安全与单细胞型生物起搏器相比，人类 SA 节点是一种天然的类器官。复杂的绝缘结构和异质细胞组成此外，人类 SA 节点是。配备冗余起搏器部位和传导通路，以保护节律免受不利影响因此，受SA节点结构和故障安全机制的启发，我们的目标是增强变时性刺激。自动化和SA传导的鲁棒性：首先，我们将重点提高SA的自动化程度通过识别起搏器膜和钙时钟蛋白、细胞的表达，节点类器官其次，我们将集中精力改善 SA 节点类器官的传导。通过协调多个起搏器部位和传导通路（目标 2）。 SA 结类器官在体外环境和体内房室传导阻滞啮齿动物模型中的稳健性（目标 3）。这些研究将确定组织水平结构和多细胞成分是否介导 SA 节点的稳健性起搏和传导，并可能揭示高保真组织级生物起搏器作为一种新型所提出的类器官将适用于人类临床前治疗。加速药物开发的化验测试，用于剖析患者特定的窦房结疾病病理生理学，以及用于开发植入式生物起搏器。