Forcing the sinoatrial node pacemaker function

强制窦房结起搏器功能

• 批准号: 10659980
• 负责人: Deborah K Lieu
• 金额: $ 40万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-26 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659980
• 关键词: Adherens Junction; Affect; Age Years; Aging; Binding; Biochemical; Biomechanics; Biosensor; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell membrane; Cells; Clinical; Collagen; Complex; Data; Development; Electronics; Engineering; Environment; Exposure to; Extracellular Matrix; Fascia adherens; Felis catus; Focal Adhesion Kinase 1; Functional disorder; Future; Gap Junctions; Gene Expression; Goals; HCN4 gene; Human; Implant; In Vitro; Integrins; Intercellular Junctions; Left; Left ventricular structure; Ligands; Maintenance; Mass Spectrum Analysis; Mediating; Microscopy; N-Cadherin; Pacemakers; Patients; Periodicity; Persons; Phenotype; Prevention strategy; Preventive measure; Property; Protein Isoforms; Proteins; Reporting; Role; Shapes; Signal Transduction; Signaling Protein; Sinoatrial Node; Sinus; Source; Testing; Therapeutic; Tissues; Ventricular; cellular engineering; density; design; fetal; gain of function; heart rhythm; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; insight; loss of function; mechanical force; mechanical properties; mechanotransduction; member; novel; novel therapeutic intervention; novel therapeutics; protein degradation; transmission process

PROJECT SUMMARY Pacemaking sinoatrial node (SAN) that orchestrates the heart rhythm can become dysfunctional with aging. Biopacemakers composed of human induced pluripotent stem cell (hiPSC)-derived pacemaking cardiomyocytes (P-CMs) can be one therapeutic strategy that can restore the sinus rhythm in patients suffering from SAN dysfunction. The development of biopacemakers is hampered by issues such as low differentiation yield of P- CMs from hiPSCs and the long-term maintenance of the pacemaking function in engineered pacemaking tissues. The function and phenotype of P-CMs can be affected by mechanical forces imposed by the extracellular matrix (ECM) forming the cellular microenvironment and the cyclic strain due to cardiac contractions. The ECM has been well demonstrated for shaping the phenotype of the working CMs. Hence, an optimal ECM should also promote and sustain pacemaking function in P-CMs. We have data demonstrating that ECM of the SAN can better sustain the pacemaking phenotype in hiPSC-derived CMs even when subjected to cyclic strain compared to the left ventricular counterpart but the exact mechanisms that induce and maintain the pacemaking phenotype are unclear. The goal of this project is to understand the mechanisms of mechanotransduction in P-CMs that can be modulated by the ECM. We hypothesize that the SAN ECM may modulate the mechanotransduction in resident P-CMs via cell-ECM junctions at the costameres and the cell-cell junctions at the fascia adherens to maintain the pacemaking phenotype. To test the mechanistic underpinnings of our hypothesis, we propose the following three aims: 1) to determine the cell-ECM-mediated mechanotransduction signaling in P-CMs, 2) to determine the cell-cell-mediated mechanotransduction signaling in the P-CMs, and 3) to determine the integrated cell-ECM and cell-cell junction network in mechanotransduction signaling in the P-CMs. A better understanding of the mechanotransduction mechanisms in P-CMs can yield a source of human P-CMs from hiPSCs with long- term pacemaking function, a set of microenvironmental criteria necessary for engineering sustainable biopacemakers and inspire future new therapeutic or preventive strategies for SAN dysfunction.

项目摘要 协调心脏节律的起搏窦房结（SAN）可能会随着年龄的增长而功能失调。 由人诱导多能干细胞（hiPSC）衍生的起搏心肌细胞组成的生物起搏器 （P-CM）可以是一种可以恢复患有SAN的患者的窦性心律的治疗策略 功能障碍生物酶制剂的发展受到诸如P- 来自hiPSC的CM和工程化起搏组织中起搏功能的长期维持。 P-CM的功能和表型可以受到细胞外基质施加的机械力的影响 (ECM)形成细胞微环境和由于心脏收缩引起的循环应变。ECM已 已经很好地证明了用于塑造工作CM的表型。因此，最佳ECM还应 促进和维持P-CM的起搏功能。我们有数据表明，SAN的ECM可以 即使在经受循环性应变时， 但是诱导和维持起搏表型的确切机制 不清楚。本项目的目标是了解P-CM中的机械传导机制， 可以由ECM调节。我们假设SAN ECM可能调节了 常驻P-CM通过肋肌处的细胞-ECM连接和附着筋膜处的细胞-细胞连接， 维持起搏表型。为了检验我们假设的机械基础，我们提出了 以下三个目的：1）确定P-CM中细胞-ECM-介导的机械转导信号，2） 确定P-CM中的细胞-细胞介导的机械转导信号传导，以及3）确定整合的 细胞-ECM和细胞-细胞连接网络在P-CM中的机械转导信号传导中的作用。更好地理解 P-CM中的机械转导机制可以从hiPSC产生人P-CM的来源， 术语起搏功能，一套工程可持续发展所必需的微环境标准 生物起搏器和启发未来新的治疗或预防战略的SAN功能障碍。