权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Beta-Adrenergic Control of the Pathological Cardiac Microtubule Network

病理性心脏微管网络的β-肾上腺素能控制

基本信息

批准号：
7952783
负责人：
GEORGE COOPER
金额：
$ 22.13万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7952783
关键词：
Adenosine Admission activity Adrenergic Agents Adrenergic Antagonists Affect Aftercare Age American Attenuated Binding Biopsy Canis familiaris Cardiac Cardiac Myocytes Catecholamines Cell Nucleolus Cell Nucleus Cells Characteristics Chronic Clinical Treatment Colchicine Congestive Heart Failure Control Animal Coupled Cytoskeleton Data Dependence Depressed mood Development Electrons Employee Strikes Etiology Failure Family Felidae Felis catus Functional disorder Genetic Transcription Genetic screening method Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hospitals Human Hypertrophy Institutes Intracellular Transport Kinesin Knowledge Left Left Ventricular Mass Left ventricular structure MAP4 Measures Mechanics Mediating Microfilaments Microtubule Depolymerization Microtubules Modeling Motor Myocardial Myocardium Myofibrils Normal Cell Outcome Patients Pharmaceutical Preparations Phase Phenotype Phosphoric Monoester Hydrolases Physiological Prevention Protein Biosynthesis Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Publishing Research Ribosomes Right ventricular structure Right-On Role Sarcomeres Science Series Site Specificity Staining method Stains Stress Structural Protein System Systolic heart failure Time Transport Process Tubulin Ventricular Work adrenergic aged base density early onset editorial experience hemodynamics interest messenger ribonucleoprotein p21 activated kinase p21-activated kinase 1 pressure prevent public health relevance relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): Our studies of the load-specificity of pathological versus physiological hypertrophic cardiac responses to hemodynamic challenges led to the discovery [Science, 260: 682-687, 1993] of a dense cardiocyte microtubule network during pathological, high ventricular wall stress hypertrophy caused by severe pressure-overloading that contributes to the striking contractile and intracellular transport dysfunction that occur in this setting. In attempting to identify the cause for this cytoskeletal abnormality, a crucial hint was provided by the fact that we have never seen microtubule network changes with an equivalent degree and duration of fully compensated physiological hypertrophy wherein ventricular wall stress remains normal. This hint, coupled with the following three further considerations, led to the studies proposed in this application. First, a hallmark of decompensated pathological cardiac hypertrophy is a persistent elevation of circulating and neural catecholamines, such that one would expect this to be present in pathological hypertrophy but absent from compensated physiological hypertrophy. Second, very recent data establish a critical role of b-adrenergic input in increasing the activity of p21-activated kinase, or Pak1, which in turn initiates a cascade of phosphatase activation, specifically of PP2A and then PP1, in the heart. Third, our own data indicate that the abnormal microtubule network seen in pathological cardiac hypertrophy is driven by binding to microtubules of MAP4, the predominant cardiac microtubule-associated structural protein, and that this in turn is driven by phosphatase-dependent site-specific MAP4 dephosphorylation. We propose to use this information here in two specific aims. In Specific Aim #1, we will attempt to establish the etiological role of b-adrenergic input in causing the hypertrophy- associated cardiac microtubule phenotype by comparing our very well characterized model of feline physiological volume-overload hypertrophy to our equally well characterized model of pathological pressure-overload hypertrophy with or without chronic b-adrenergic blockade. If correct, our hypothesis would predict that the abnormal microtubule network will be present in pressure-overload hypertrophy without b-adrenergic blockade but absent both in this model with b-adrenergic blockade and in the physiological volume-overload model with no drug treatment. In Specific Aim #2, if we are able in the previous aim to prevent formation of the dense, MAP4-decorated microtubule network by using chronic b-adrenergic blockade in the severe pressure-overload model of which it is characteristic, we will determine whether this also prevents the associated functional abnormalities of contraction and microtubule-based transport. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the leading cause of hospital admission and readmission in Americans aged 65 or greater. The contractile dysfunction and cardiac growth abnormalities that characterize systolic heart failure are a maladaptive myocardial response to several pathological challenges, including sustained cardiac pressure overloading. This study will identify the mechanism underlying one important cause for this dysfunction in the failing heart: alterations in the microtubule network of the cardiac muscle cell cytoskeleton.

描述（由申请人提供）：我们对血液动力学挑战下病理性和生理性肥厚心脏反应的负荷特异性的研究导致发现[Science， 260: 682-687, 1993]在严重压力过载引起的病理性高心室壁应激性肥厚期间存在致密的心肌微管网络，这有助于在这种情况下发生显著的收缩和细胞内运输功能障碍。在试图确定这种细胞骨架异常的原因时，一个关键的提示是，我们从未见过微管网络的变化与完全代偿的生理肥厚的程度和持续时间相当，其中心室壁压力保持正常。这个提示，再加上以下三个进一步的考虑，导致了本应用程序中提出的研究。首先，失代偿性病理性心脏肥厚的一个标志是循环和神经儿茶酚胺的持续升高，因此人们会期望这在病理性肥厚中存在，但在代偿性肥厚中不存在。其次，最近的数据证实了b-肾上腺素能输入在增加p21活化激酶（Pak1）活性方面的关键作用，这反过来又启动了磷酸酶的级联激活，特别是PP2A和PP1，在心脏中。第三，我们自己的数据表明，病理性心脏肥大中出现的异常微管网络是由与MAP4（主要的心脏微管相关结构蛋白）的微管结合驱动的，而这反过来又是由磷酸酶依赖的位点特异性MAP4去磷酸化驱动的。我们建议在两个具体目标中使用这一信息。在Specific Aim #1中，我们将通过比较我们非常有特征的猫生理容量过载肥大模型和我们同样有特征的有或没有慢性b-肾上腺素能阻断的病理性压力过载肥大模型，试图建立b-肾上腺素能输入在引起肥大相关的心脏微管表型中的病因学作用。如果正确，我们的假设将预测在没有b-肾上腺素能阻断的压力过载肥大中存在异常微管网络，但在有b-肾上腺素能阻断的模型和没有药物治疗的生理容量过载模型中都不存在异常微管网络。在特定目标#2中，如果我们能够在先前的目标中通过在严重压力过载模型中使用慢性b-肾上腺素能阻断来防止密集的、map4修饰的微管网络的形成，我们将确定这是否也可以防止相关的收缩和微管运输的功能异常。