Control of Cardiac Function by Calcium and Myofilaments

钙和肌丝对心脏功能的控制

• 批准号: 6970292
• 负责人: BEATA M. WOLSKA
• 金额: $ 34.13万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970292
• 关键词: beta adrenergic receptor; calcium flux; calcium transporting ATPase; cardiac myocytes; gene mutation; heart failure; heart function; hypertrophic myocardiopathy; laboratory mouse; microfilaments; pharmacogenetics; phospholamban; phosphorylation; sarcoplasmic reticulum; tissue /cell culture; tropomyosin

DESCRIPTION (provided by applicant): Our long-term objective is to understand the relative role of Ca2+ and myofilaments in the regulation of cardiac function under normal and pathological conditions such as hypertrophy and heart failure (HF). In the current proposal we will focus on genetically linked hypertrophy, hypertrophic cardiomyopathy (HCM). We hypothesize that if HCM is associated with increased myofilament sensitivity to Ca2+ and diastolic dysfunction, then pathological cardiac hypertrophy and cardiac dysfunction can be delayed or prevented by short and long-term interventions in Ca2+ regulation. We also hypothesize that the increased myofilament sensitivity to Ca2+ that is observed in HCM is also associated with alterations in beta-adrenergic receptor mediated pathways resulting in altered myofilament and sarcoplasmic reticulum (SR) protein phosphorylation, which are all important elements in the development of hypertrophy and HF in general. We will test the hypothesis that increasing SR Ca2+ uptake by increased expression of SR Ca2+ pump (SERCA2a; Aim 1) or by phospholamban knockout (Aim 2) will delay the development of hypertrophy and improve heart function in HCM linked mutations in regulatory proteins such as tropomyosin (TM) or troponin T (TnT) that show increased myofilament sensitivity to Ca2+ and diastolic dysfunction. In Aim 3 we will determine the role of altered myofilament and sarcoplasmic reticulum beta-adrenergic receptor mediated protein phosphorylation in the development of hypertrophy in the same HCM linked mutations in regulatory proteins. In summary we seek to better understand the role of increased myofilament sensitivity to Ca2+ in development of hypertrophy in HCM and to test the hypothesis that increasing SR Ca2+ uptake my overcome the increased myofilament sensitivity to Ca2+, restore normal diastolic function, and in the long term delay the development of hypertrophy and cardiac dysfunction. Therefore, the current proposal may have potential clinical applications.

描述（由申请人提供）：我们的长期目标是了解在正常和病理状况（例如肥大和心力衰竭（HF））下Ca2+和肌膜在心脏功能调节中的相对作用。 在当前的提案中，我们将重点关注遗传联系的肥厚肥厚，肥厚性心肌病（HCM）。 我们假设，如果HCM与CA2+和舒张功能障碍的肌丝敏感性增加有关，则可以通过CA2+调节的短期和长期干预延迟或预防病理心脏肥大和心脏功能障碍。 我们还假设，在HCM中观察到的对Ca2+的肌丝敏感性的提高也与β-肾上腺素能受体介导的途径的改变有关，从而改变了肌膜和肌胞质网状（SR）蛋白质磷酸化的改变，这都是在超高和HF中的重要元素。 我们将测试以下假设：通过增加SR Ca2+泵表达（SERCA2A; AIM 1）或通过磷脂敲除（AIM 2）来增加SR Ca2+摄取（AIM 2）将延迟肥大的发展，并改善HCM连接的在调节蛋白（如曲霉菌素）（TM）+ toconin tont（TM）TTNT（TM）TNT（TM）中的链接性突变（TTNT+），从而显示了增强的（TM）TT（TM）TT（TM）TOROFILANT（TM）TTS（TM）TORMONTIN（TM）TORMONTIN（TM）TORITANT（TM）TORITAINS（TM）TORMONT（TM）TORITANT（TM）功能障碍。 在AIM 3中，我们将确定改变肌丝和肌浆网β-肾上腺素能受体介导的蛋白磷酸化在调节蛋白中相同HCM连接的突变中肥大的发展中的作用。 总而言之，我们试图更好地了解HCM中对Ca2+肌细丝敏感性提高的作用，并测试以下假设：增加了SR Ca2+摄取量的增加，我克服了对Ca2+的肌膜敏感性的增加，对Ca2+的敏感性增加，恢复正常的舒张功能，以及长期延迟了超级型和心脏外生的发育。 因此，当前的建议可能具有潜在的临床应用。