Thyroid hormone regulation of cardiomyocyte T-tubule structureand function

甲状腺激素对心肌细胞T管结构和功能的调节

• 批准号: 10046567
• 负责人: Kaie Margareeta OJAMAA
• 金额: $ 42.84万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046567
• 关键词: Adrenergic Agents; Adult; Animal Model; Animals; Atrophic; Attenuated; Award; Calcium; Caliber; Cardiac; Cardiac Myocytes; Cell Survival; Cell physiology; Chemicals; Chronic Disease; Clinical Research; Confocal Microscopy; Coupling; Data; Development; Disease; Disease model; Dose; Echocardiography; Educational process of instructing; Ensure; Environment; Exposure to; Functional disorder; Genes; Genetic Transcription; Glucocorticoids; Goals; Growth; Heart Diseases; Heart failure; Hormones; Human; Hypertension; Hypothyroidism; Image; Impairment; Infarction; Institution; Ion Channel; Ischemia; Kinetics; Learning; Length; Life; Low T3 Syndromes; Mammals; Measures; Medical; MicroRNAs; Microscopy; Modeling; Molecular; Movement; Muscle Cells; Myocardial Infarction; Neonatal; Oral; Patient Care; Patients; Periodicity; Phenotype; Process; Production; Propylthiouracil; Proteins; Rattus; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Ryanodine Receptors; Sarcomeres; Sarcoplasmic Reticulum; Science; Series; Serum; Signal Transduction; Structure; Students; Supplementation; System; Testing; Therapeutic; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyronines; Tissues; Ventricular; Work; cardiac tissue engineering; cellular imaging; clinically relevant; clinically significant; confocal imaging; diabetic cardiomyopathy; experience; experimental study; heart function; hemodynamics; hormonal signals; hormone deficiency; hormone metabolism; hormone regulation; hormone therapy; improved; induced pluripotent stem cell; insight; junctophilin; molecular imaging; novel; outcome forecast; response; single molecule; stem cells; transcriptome sequencing

Project summary/abstract Chronic diseases including heart failure (HF) often present with thyroid dysfunction. Evidence from animal and human studies of HF provide strong evidence that low thyroid hormones (TH) contribute to poor prognosis and that TH treatment improves measures of cardiac function. Experimental studies of heart diseases due to ischemia and hypertension, or diabetic cardiomyopathy, all induce low cardiac tissue T3 (bioactive TH) concentrations that we propose is the primary cause of myocyte dysfunction. T3 regulates many cellular processes including transcription of cardiac genes regulating calcium and contractility, cell survival, growth, adrenergic and ion channel activities. We hypothesize that T3 regulates T-tubule (TT) structures in cardiomyocytes, and that impaired T3 signaling leads to adverse TT remodeling and contractile dysfunction. This concept is supported by recent studies indicating an essential requirement of THs in the development of a functioning TT network in the transition from structurally immature neonatal to adult cardiomyocytes. Advancements in super-resolution imaging have confirmed that adverse remodeling of TT occurs in cardiomyocytes from patients and animal models of HF leading to impaired excitation- contraction (EC)-coupling. Our preliminary data show that cardiomyocyte TT periodicity is significantly reduced in MI-induced heart failure and TH-deficient animal models, causing slower calcium kinetics and contractility. The overarching goal of this work is to provide rigorous scientific evidence to support a therapeutic benefit in normalizing TH function in patients with heart failure. To accomplish this goal, we propose to study two disease models of thyroid dysfunction: (1) heart failure induced by myocardial infarction (MI), and (2) TH-deficiency produced by chemical (PTU) inhibition of TH production. In the HF model, oral treatment with replacement-dose T3 will be initiated immediately after MI and continued for 16 weeks. Ca2+ transients and contractility will be recorded from isolated ventricular myocytes, and T3 effects on TT remodeling will be assessed by confocal microscopy. We will use multi-wavelength super-resolution single-molecule imaging that is currently the best approach to quantify potential T3-induced changes in distribution of Ca2+ handling proteins (Ryanodine receptors, L-type Ca2+ channels, Bridging Integrator-1, Junctophilin-2). In the TH-deficient model, effects of short-term T3 treatment alone on TT periodicity, clustering of Ca2+ proteins and contractile function will be similarly assessed. Interrogation of the molecular mechanisms underlying the TT remodeling responses to T3 will involve cultured adult ventricular myocytes, and expressed gene studies including RNAseq approaches. Results from this study have the potential to advance treatment options for the patient with HF presenting with low serum THs. Support of this proposal by REAP will promote the research environment at NYIT, and provide opportunities for our students to participate in clinically relevant research that may change the course of patient care.

项目概要/摘要 包括心力衰竭（HF）在内的慢性疾病常伴有甲状腺功能障碍。动物证据 对HF和人类的研究提供了强有力的证据，表明低甲状腺激素（TH）有助于不良的 预后和TH治疗改善心脏功能的措施。心脏实验研究 由于局部缺血和高血压或糖尿病性心肌病引起的疾病，都引起低心脏组织T3 我们认为（生物活性TH）浓度是肌细胞功能障碍的主要原因。T3调节 许多细胞过程包括调节钙和收缩性的心脏基因的转录，细胞 存活、生长、肾上腺素能和离子通道活性。我们假设T3调节T-小管（TT） 心肌细胞中的结构，受损的T3信号传导导致不利的TT重塑， 收缩功能障碍这一概念得到了最近研究的支持，研究表明， 在从结构不成熟的新生儿向结构不成熟的新生儿过渡的过程中， 成年心肌细胞超分辨率成像的进展已经证实， TT发生在HF患者和动物模型的心肌细胞中，导致兴奋受损- 收缩（EC）偶联。我们的初步数据显示，心肌细胞TT周期性显著增加， 在MI诱导的心力衰竭和TH缺乏动物模型中减少，导致钙动力学减慢， 收缩性这项工作的首要目标是提供严格的科学证据，以支持一个 在心力衰竭患者中使TH功能正常化的治疗益处。为了实现这一目标， 我们拟研究两种甲状腺功能障碍的疾病模型：（1）心肌梗死引起的心力衰竭， 梗死（MI）和（2）TH产生的化学抑制（PTU）引起的TH缺乏。在HF 模型，MI后立即开始口服剂量T3治疗，持续16 周将从分离的心室肌细胞记录Ca 2+瞬变和收缩性，并记录T3效应 将通过共聚焦显微镜评估对TT重塑的影响。我们将使用多波长超分辨率 单分子成像是目前量化潜在T3诱导的变化的最佳方法， Ca 2+处理蛋白（Ryanodine受体，L-型Ca 2+通道，桥接整合子-1， 嗜连接蛋白-2）。在TH缺乏模型中，短期T3单独治疗对TT周期性的影响， 将类似地评估Ca 2+蛋白的聚集和收缩功能。分子的审问 对T3的TT重塑反应的潜在机制将涉及培养的成年心室肌细胞， 和表达基因研究，包括RNAseq方法。这项研究的结果有可能 为出现低血清TH的HF患者提供先进的治疗选择。支持这一提议 REAP将促进NYIT的研究环境，并为我们的学生提供机会， 参与可能改变患者护理过程的临床相关研究。

项目成果

Triiodothyronine maintains cardiac transverse-tubule structure and function.

• DOI: 10.1016/j.yjmcc.2021.06.010
• 发表时间: 2021-11
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Gilani N;Wang K;Muncan A;Peter J;An S;Bhatti S;Pandya K;Zhang Y;Tang YD;Gerdes AM;Stout RF;Ojamaa K
• 通讯作者: Ojamaa K