Troponin Modulation in Heart Failure

心力衰竭中的肌钙蛋白调节

• 批准号: 8005569
• 负责人: R John Solaro
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005569
• 关键词: Address; Adverse effects; Affect; Animal Model; Attenuated; Blood; Calcium; Cardiac; Cardiomyopathies; Complex; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diagnostic; Equilibrium; Familial Hypertrophic Cardiomyopathy; Figs - dietary; Functional disorder; Funding; Heart; Heart Diseases; Heart failure; Hypertrophic Cardiomyopathy; Hypertrophy; In Situ; In Vitro; Investigation; Knowledge; Lead; Link; Lipids; MAP Kinase Gene; MAPK14 gene; Medicine; Microfilaments; Modification; Mutation; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Protein Dephosphorylation; Protein phosphatase; Proteins; Publishing; Recording of previous events; Regulation; Relative (related person); Ryanodine Receptor Calcium Release Channel; Signal Transduction; Site; Sphingomyelins; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Translating; Translations; Tropomyosin; Troponin; Troponin I; Troponin T; desensitization; design; insight; mouse model; myosin-binding protein C; novel; p21 activated kinase; pressure; prevent; public health relevance; receptor; research study; response; rho; therapeutic target; tool

DESCRIPTION (provided by applicant): In experiments proposed here we test the hypothesis that signaling through p21 activated kinase (Pak1) to protein phosphatase 2A (PP2A) is a novel mechanism of control of contractility by suppression of Ca-release units (CRU) in excitation contraction coupling (ECC) via effects on Ca2+ channel and ryanodine receptor function and stimulation of myofilament response to Ca2+ via sarcomeric protein dephosphorylation. Preliminary and published data in the current period of funding indicate that the function of Pak1 in integrated control of contractility involves signaling through 2-receptor/PKA phosphorylation of Pak1 and through sphingomyelin related lipid signaling that also activates Pak1. We also identified a novel mechanism of regulation of sarcomeric protein phosphorylation by various active forms of PKC6, which also acts in a signaling complex with Pak1. Aim #1 of our proposals is to test the hypothesis that the Pak1-PP2A signaling cascade is a novel mechanism of control of contractility acting by regulating the balance of CRU activity in ECC and myofilament response to Ca2+. Aim #2 is to determine the functional significance of diverse pathways of activation of PKC6 that induce dephosphorylation of cTnI and cTnT and phosphorylation of MyBP- C and Tm. Aim # 3 extends our studies on novel control of myofilament response to Ca2+ to our objective to determine if specific desensitization of the myofilaments to Ca2+ can serve as a therapeutic tool to prevent or attenuate the development of hypertrophy and dysfunction in transgenic mouse models of familial hypertrophic cardiomyopathy (HCM). Our preliminary and published data indicate that desensitization of myofilament response to calcium is able to rescue adverse effects in HCM-linked sarcomeric mutations in mouse models. Results of experiments proposed will provide insights into a previously unappreciated mode of activation of contractility, which provides new leads in translation medicine in cardiomyopathies. PUBLIC HEALTH RELEVANCE: Experiments proposed in the present application determine a new mechanism for control of the pressure developed in the heart that is responsible for ejection of blood. The new mechanism is likely to add to our understanding of heart failure, when pressure and ejection of blood is disturbed. Moreover, the new mechanism may lead to development of novel therapies for heart failure.

描述（由申请人提供）：在此处提出的实验中，我们测试了以下假说：p21激活激酶（PAK1）对蛋白质磷酸酶2a（PP2A）的信号是通过抑制Ca-Release单位（CRO）在激发co响应中对CA2+ CARPARTION对CA2+ CARINER的影响Ryyanod的刺激反应（ECC）来控制收缩力的新型机制。通过肉瘤蛋白去磷酸化。在当前资金期间的初步和已发表的数据表明，PAK1在收缩性综合控制中的功能涉及通过PAK1的2受体/PKA磷酸化以及通过鞘磷脂相关的脂质信号传导，这也激活了PAK1。我们还确定了一种通过各种活性形式的PKC6调节肌肉蛋白磷酸化的新型机制，该机制也与PAK1的信号传导复合物作用。我们的建议的目的1是检验以下假设：PAK1-PP2A信号级联是通过调节ECC和肌丝对Ca2+的肌丝反应的平衡来控制收缩力的一种新型机制。目的＃2是确定诱导CTNI和CTNT脱磷酸化的PKC6激活途径的功能意义，以及Mybp-C和TM的磷酸化。 AIM＃3扩展了我们对肌丝对Ca2+反应的新研究的研究，以确定肌细胞对Ca2+的特定脱敏是否可以作为一种治疗工具，以防止或消除家族性肥大性心脏疾病（HCM）转基因小鼠模型中肥大和功能障碍的发展。我们的初步和发布的数据表明，肌丝对钙的脱敏能力能够挽救小鼠模型中HCM连接的肉瘤突变中的不良反应。提出的实验结果将提供有关以前未批准的收缩力激活方式的见解，该模式为心肌病的翻译医学提供了新的潜在客户。 公共卫生相关性：本应用程序中提出的实验确定了控制心脏中产生的压力的新机制，该机制负责射血。当血液的压力和射血受到干扰时，新机制可能会增加我们对心力衰竭的理解。此外，新机制可能导致发展新型心力衰竭疗法。