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) 在内的慢性疾病通常伴有甲状腺功能障碍。来自动物的证据 心力衰竭的人体研究提供了强有力的证据，证明低甲状腺激素 (TH) 会导致贫困 预后以及 TH 治疗可改善心功能指标。心脏的实验研究 缺血和高血压引起的疾病，或糖尿病性心肌病，都会导致心脏组织T3降低 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，包括调节钙和收缩力的心脏基因的转录、细胞 生存、生长、肾上腺素能和离子通道活动。我们假设 T3 调节 T 管 (TT) 心肌细胞的结构，T3 信号传导受损会导致不良的 TT 重塑和 收缩功能障碍。这一概念得到了最近研究的支持，表明了一个基本要求 从结构不成熟的新生儿到功能性 TT 网络的发展过程中的 TH 成体心肌细胞。超分辨率成像的进步已经证实，不良重塑 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）耦合。我们的初步数据表明心肌细胞 TT 周期性显着 在 MI 诱发的心力衰竭和 TH 缺乏的动物模型中减少，导致钙动力学减慢， 收缩性。这项工作的总体目标是提供严格的科学证据来支持 心力衰竭患者 TH 功能正常化的治疗益处。为了实现这个目标， 我们拟研究甲状腺功能障碍的两种疾病模型：（1）心肌引起的心力衰竭 梗塞（MI），和（2）化学物质（PTU）抑制TH产生而导致TH缺乏。在高频 模型中，MI 后立即开始口服替代剂量 T3 治疗并持续 16 几周。将从分离的心室肌细胞记录 Ca2+ 瞬变和收缩性，以及 T3 效应 TT 重塑将通过共焦显微镜进行评估。我们将使用多波长超分辨率 单分子成像是目前量化 T3 诱导的潜在变化的最佳方法 Ca2+ 处理蛋白的分布（Ryanodine 受体、L 型 Ca2+ 通道、Bridging Integrator-1、 亲结蛋白-2)。在 TH 缺陷模型中，单独短期 T3 治疗对 TT 周期性的影响， Ca2+ 蛋白的聚集和收缩功能将进行类似的评估。分子质询 TT 重塑对 T3 反应的机制将涉及培养的成年心室肌细胞， 以及表达基因研究，包括 RNAseq 方法。这项研究的结果有可能 为患有低血清 TH 的心力衰竭患者提供先进的治疗方案。支持该提案 by REAP 将提升纽约理工学院的研究环境，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