Molecular Physiology of Myocardial Troponin I Variants

心肌肌钙蛋白 I 变体的分子生理学

• 批准号: 7664251
• 负责人: Anne M Murphy
• 金额: $ 50万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-13 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664251
• 关键词: Acceleration; Acute; Address; Adult; African American; Calcium; Cardiac; Cardiac Myocytes; Child; Chronic; Complex; Cyclic AMP-Dependent Protein Kinases; Defect; Development; Devices; Diastolic heart failure; Disease; Dissection; Elderly; Exons; Failure; Frequencies; Functional disorder; Goals; Grant; Heart; Heart Rate; Heart failure; Hereditary Disease; Human; Hypertension; Hypertrophy; In Vitro; Investigational Therapies; Laboratories; Link; Medical; Metabolic; Microfilaments; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Contraction; Pathologic; Pattern; Phosphorylation; Physiology; Play; Prevalence; Process; Proteins; Proteomics; Pump; Range; Recombinants; Relative (related person); Relaxation; Role; Series; Site; Staging; Syndrome; Therapeutic; Tissues; Transplantation; Troponin I; United States; Variant; Work; design; genetic regulatory protein; genetic variant; heart function; human disease; in vivo; in vivo Model; insight; interest; mortality; mouse model; novel; phospholamban; prevent; response

Contraction of the heart occurs through regulated interactions of the myofilament proteins in response to increasing intracellular calcium concentrations. In heart failure both calcium dynamics and the response of the myofilaments to calcium are altered. These alterations impair systolic and diastolic function and are potentially reversible. This proposal seeks to define specific mechanisms for the effects of variants of the key regulatory protein troponin I which contribute to heart failure and hypertrophy. The hypothesis of this proposal is that post translational or genetic variants cardiac troponin I modify its function and play a central role in heart failure and the response to increased heart rate and afterload. The long-range goal of this work is to understand the underlying molecular mechanism by which these variants alter cardiac function in order to design strategies to prevent or treat cardiac dysfunction. The dissection of the molecular pathophysiology of troponin I variants will be approached in a series of highly collaborative integrative studies focused on modeling of myofilament disease-related post translational or genetic variants changes in vivo in murine models and in human cardiomyocytes. To address these goals the following aims are proposed: 1. To determine the degree and impact of altered site-specific phosphorylation of TnI in human heart failure by quantitative phosphoproteomics in human cardiomyocytes and expression of phospo or dephospho mimics in human cardiomyoctyes 2. To determine whether phosphorylation of PKA sites of troponin I or phospholamban are the dominant contributor to the in vivo frequency dependent acceleration of relaxation (FDAR) and the relaxation response to afterload by use of interbred mouse models and 3. To address the hypothesis that an exon 5 sequence variant of troponin I, which occurs with a 3 % frequency in African-Americans, influences the response to acute and chronic afterload through the use of an in vivo murine model. This work should provide insight into the in vivo effects of specific myofilament troponin I variants which contribute to pathophysiology of heart failure and hypertrophy. In the long-term this will assist in the development of novel therapies which address the correction of myofilament defects.

心脏收缩是通过肌丝蛋白响应于调节的相互作用而发生的 增加细胞内钙浓度。在心力衰竭中，钙动力学和反应 肌丝的钙含量发生改变。这些改变会损害收缩和舒张功能， 可能是可逆的。该提案旨在定义不同变体影响的具体机制。 导致心力衰竭和肥厚的关键调节蛋白肌钙蛋白 I。对此的假设 建议翻译后或遗传变异心肌肌钙蛋白 I 改变其功能并发挥核心作用 在心力衰竭以及对心率和后负荷增加的反应中的作用。本次活动的远期目标 工作是了解这些变异改变心脏功能的潜在分子机制 以便设计预防或治疗心脏功能障碍的策略。分子的剖析 肌钙蛋白 I 变体的病理生理学将通过一系列高度协作的综合研究来研究 研究重点是肌丝疾病相关的翻译后或遗传变异变化的建模 小鼠模型和人类心肌细胞体内。为了实现这些目标，以下目标是 建议： 1. 确定人类 TnI 位点特异性磷酸化改变的程度和影响 通过人心肌细胞中的定量磷酸蛋白质组学和磷酸或磷酸盐的表达来研究心力衰竭 人心肌细胞中的去磷酸模拟物 2. 确定 PKA 位点是否磷酸化 肌钙蛋白 I 或受磷蛋白是体内频率依赖性加速度的主要贡献者 3. 使用杂交小鼠模型测定松弛度 (FDAR) 和对后负荷的松弛反应 解决肌钙蛋白 I 的外显子 5 序列变体的假设，该变体以 3% 的频率出现在 非裔美国人，通过体内使用影响对急性和慢性后负荷的反应 小鼠模型。这项工作应该可以深入了解特定肌丝肌钙蛋白 I 的体内作用 导致心力衰竭和肥厚病理生理学的变异。从长远来看，这将 协助开发解决肌丝缺陷纠正的新疗法。