Defining Novel Cardiovascular Mechanisms For TKI Induced Excitability

定义 TKI 诱导兴奋性的新心血管机制

• 批准号: 10677861
• 负责人: Sakima Ahmad Smith
• 金额: $ 40.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677861
• 关键词: Ablation; Action Potentials; Animal Model; Animals; Apoptosis; Arrhythmia; Calmodulin; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiotonic Agents; Cardiotoxicity; Cardiovascular system; Cause of Death; Cells; Cessation of life; Data; Defect; Dimethyl Sulfoxide; Drug usage; Elderly; Electrocardiogram; Electrophysiology (science); Event; FDA approved; Fibrosis; Functional disorder; Genes; Glucose; Growth; Heart; Heart failure; Homeostasis; Human; Impairment; In Vitro; Incidence; Ion Channel; Ions; Isoproterenol; Lead; Life; Malignant Neoplasms; Maps; Marketing; Mitochondria; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial dysfunction; Optics; Organ; Pathogenicity; Pathologic; Pathway interactions; Patient Agents; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Population; Prevalence; Production; Proteins; Reactive Oxygen Species; Renal Cell Carcinoma; Renal carcinoma; Role; Signal Pathway; Signal Transduction; Sodium; Stress; Testing; Therapeutic; Time; Transcript; Transgenic Mice; Translating; Treatment Efficacy; Treatment-Related Cancer; Tyrosine Kinase Inhibitor; Ventricular; Wild Type Mouse; Work; anticancer treatment; cardioprotection; clinical decision-making; experimental study; improved; in vivo; induced pluripotent stem cell; inhibitor; inhibitor therapy; innovation; mortality; novel; oxidation; prevent; side effect; success; symporter; voltage

Project Summary/Abstract The 14 million cancer survivors living in the US clearly demonstrate continued improvements in anti- cancer treatment efficacy; yet, this success has been tempered by a parallel rise in the incidence of cancer treatment-related cardiotoxicity, leading to morbidity and mortality. A prominent example of this conundrum involves Tyrosine Kinase Inhibitors (TKIs), first-line therapy in kidney cancer, the 16th most common cause of death worldwide. Renal cell carcinoma (RCC) accounts for approximately 90% of all cases with ~143,000 deaths/year. The incidence and prevalence of RCC have been increasing over the last 50 years, and with the growth of the US elderly population, these numbers will only continue to increase. Mounting data support that TKIs can modify and inhibit cardiac voltage-gated Na+ channel Nav1.5, and in general play a key role in cardiac excitability. At the same time, TKIs have been shown to increase reactive oxygen species (ROS) in cardiomyocytes. In turn, ROS is known to activate the multifunctional Ca2+/calmodulin- dependent kinase II (CaMKII), which resides at the hub of a pro-arrhythmia signaling hub in cardiac myocytes. In previous work, we have shown that CaMKII promotes arrhythmia in part through direct phosphorylation of Nav1.5 at Ser571 with a concomitant increase in INa,L. Notably, INa,L has importance in regulating contractility in normal heart, thus of all the potential ion channels to target for cardioprotection, INa,L inhibition could prevent arrhythmias and adverse structural remodeling in patients taking TKIs. Based on these data, we will test the hypothesis that TKI-induced arrhythmia acts in part through oxidative activation of CaMKII and increased excitability cardiac myocytes. Thus, we propose INa,L is an attractive target to prevent TKI induced cardiotoxicity Results will inform clinical decision making regarding drug-induced arrhythmias, inform mechanistic approaches to prevent Ca2+ overload, and define an innovative approach using drugs readily available on the market as cardioprotective agents for patients during TKI therapy. We propose to: 1) Determine the role of TKIs in modulating cardiac myocyte excitability 2) Define the impact of TKIs on cardiac phenotypes, and 3) Define potential therapeutic strategies that mitigate TKI-induced cardiac dysfunction.

项目概要/摘要 生活在美国的 1400 万癌症幸存者清楚地表明，抗癌能力不断提高。 癌症治疗功效；然而，癌症发病率的同步上升却削弱了这一成功 治疗相关的心脏毒性，导致发病率和死亡率。这个难题的一个突出例子 涉及酪氨酸激酶抑制剂 (TKI)，这是肾癌的一线治疗方法，肾癌是肾癌第 16 位最常见的病因 全世界的死亡。肾细胞癌 (RCC) 约占所有病例的 90%，约有 143,000 例 死亡人数/年。过去 50 年来，RCC 的发病率和患病率一直在增加，并且随着 随着美国老年人口的增长，这些数字只会继续增加。 越来越多的数据支持 TKI 可以修改和抑制心脏电压门控 Na+ 通道 Nav1.5，以及 一般来说，在心脏兴奋性中起关键作用。同时，TKI 已被证明可以增加反应性 心肌细胞中的氧物质（ROS）。反过来，ROS 会激活多功能 Ca2+/钙调蛋白- 依赖性激酶 II (CaMKII)，位于心肌细胞中促心律失常信号传导中枢的中心。 在之前的工作中，我们已经证明 CaMKII 部分通过直接磷酸化促进心律失常 Ser571 处的 Nav1.5 伴随着 INa,L 的增加。值得注意的是，INa,L 在调节收缩力方面具有重要意义 正常心脏，因此在所有潜在的心脏保护目标离子通道中，INa,L 抑制可以预防 服用 TKI 的患者出现心律失常和不良结构重塑。根据这些数据，我们将测试 假设 TKI 诱导的心律失常部分通过 CaMKII 的氧化激活和增加 心肌细胞的兴奋性。因此，我们认为 INa,L 是预防 TKI 引起的心脏毒性的一个有吸引力的靶点 结果将为有关药物引起的心律失常的临床决策提供信息，并为机制提供信息 预防 Ca2+ 超载的方法，并使用现有药物定义创新方法 作为 TKI 治疗期间患者的心脏保护剂上市。我们建议： 1) 确定 TKI 的作用 调节心肌细胞兴奋性 2) 定义 TKI 对心脏表型的影响，以及 3) 定义 减轻 TKI 引起的心脏功能障碍的潜在治疗策略。