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.

项目摘要/摘要 居住在美国的1400万癌症幸存者清楚地表明了反抗 癌症治疗功效；然而，癌症发生率的平行升高使这种成功得到了缓解 与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的例子 涉及酪氨酸激酶抑制剂（TKI），肾癌的一线治疗，是第16个最常见的原因 全球死亡。肾细胞癌（RCC）约占所有约143,000例的90％ 死亡/年。在过去的50年中，RCC的发病率和患病率一直在增加，随着 美国老年人口的增长，这些数字只会继续增加。 TKIS可以修改和抑制心脏电压门控的NA+通道NAV1.5的安装数据支持，并且 总的来说，在心脏兴奋性中起关键作用。同时，已显示TKI会增加反应性 心肌细胞中的氧（ROS）。反过来，ROS被称为激活多功能Ca2+/钙调蛋白 - 依赖性激酶II（CAMKII）位于心肌细胞中心律失常信号中心的枢纽。 在先前的工作中，我们表明CAMKII通过直接磷酸化促进心律失常 nav1.5在Ser571，ina，l。值得注意的是，ina，L在调节收缩性方面很重要 正常的心脏，因此，在所有潜在的离子通道中靶向心脏保护的目标，ina，l抑制可以防止 服用TKI的患者的心律失常和不良结构重塑。基于这些数据，我们将测试 假设TKI诱导的心律不齐部分通过CAMKII的氧化激活而起作用并增加 兴奋性心肌细胞。因此，我们提出INA，L是防止TKI诱导心脏毒性的有吸引力的目标。 结果将为有关药物引起的心律不齐的临床决策提供信息，并为机械提供信息 防止CA2+超负荷的方法，并使用随时可用的药物来定义一种创新的方法 在TKI治疗期间，市场作为患者的心脏保护剂。我们建议：1）确定TKI的作用 在调节心肌兴奋性2）定义TKI对心脏表型的影响，3）定义 潜在的治疗策略减轻TKI诱导心脏功能障碍。