MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY

MAP4 心脏微管网络密度的调节

• 批准号: 8063058
• 负责人: GEORGE COOPER
• 金额: $ 36.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063058
• 关键词: Accounting; Acidic Region; Admission activity; Adult; Affinity; Agonist; Ally; Alzheimer' s Disease; American; Amino Acid Repetitive Sequences; Amino Acids; Animal Model; Appearance; Area; Atrial Heart Septal Defects; Binding; Binding Sites; Brain; Cardiac; Cardiac Myocytes; Catalytic Domain; Cells; Cellular Morphology; Chimeric Proteins; Chronic Disease; Complex; Congestive Heart Failure; Cytoskeleton; Data; Defect; Development; Disease; Dissociation; Employee Strikes; Enzymes; Exhibits; Failure; Family; Family Felidae; Feedback; Fiber; Functional disorder; G-Protein Signaling Pathway; Gene Transfer Techniques; Generations; Genes; Glycogen Synthase Kinase 3; Goals; Grant; Growth; Guanosine Triphosphate; Heart; Heart Hypertrophy; Heart failure; Holoenzymes; Homeostasis; Hospitals; Human; Hypertrophy; Image; In Vitro; Infection; Intracellular Transport; Lead; Left Ventricular Hypertrophy; Lytic; MAP4; Mediating; Microfilaments; Microtubule Depolymerization; Microtubule-Associated Proteins; Microtubules; Mitogen-Activated Protein Kinases; Mitosis; Mitotic spindle; Modeling; Molecular; Monomeric GTP-Binding Proteins; Motion; Muscle; Myocardial; Myocardium; Myofibrils; Myosin Heavy Chains; N-terminal; Neurofibrillary Tangles; Neurons; Oranges; Pathology; Phenotype; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Proline; Proline-Rich Domain; Property; Protein Dephosphorylation; Protein Family; Protein Isoforms; Protein Kinase C; Protein phosphatase; Proteins; Pulmonary artery structure; Regulation; Research; Resistance; Role; Sarcomeres; Sarcoplasmic Reticulum; Serine; Serine Phosphorylation Site; Signal Transduction; Site; Stress; Structural Protein; Structure; Systolic heart failure; Tail; Tandem Repeat Sequences; Tissues; Transgenic Mice; Tubulin; Up-Regulation; Ventricular; Viscosity; Wild Type Mouse; Work; aged; base; density; dimer; disease characteristic; genetic regulatory protein; in vivo; inhibitor/antagonist; interest; link protein; mRNA Stability; member; overexpression; p21-activated kinase 1; paired helical filament; phosphoinositide-dependent kinase 1; pressure; promoter; public health relevance; receptor coupling; response; tau Proteins; trafficking

DESCRIPTION (provided by applicant): We have shown at the levels of isolated cell, isolated tissue and the intact heart in vivo that increased microtubule network density is one cause of contractile dysfunction in high wall stress right or left ventricular hypertrophy. We then showed that increased affinity of microtubule-associated protein 4 [MAP4] for microtubules is the primary determinant of hypertrophy-related microtubule network sta- bilization and densification, and is thereby responsible for both the contractile dysfunction and associ- ated defects in microtubule-based intracellular trafficking that we have also described in this setting. MAP4 phosphorylation status appears to determine MAP4 affinity for microtubules. Therefore, this application intends to characterize the persistent changes in site-specific MAP4 phosphorylation status in an animal model of pathological pressure overload hypertrophy, with a parallel model of physiologi- cal volume overload hypertrophy serving as a control for any effects of growth per se. We will then delineate the regulation of MAP4 phosphorylation by examining relevant kinases and phosphatases. We believe that the successful execution of the proposed research will likely generate important new information to help understand the cellular and molecular mechanisms underlying cardiac hypertro- phy and failure. In addition, while our own end point of interest is the microtubule, the persistent increase in cardiac phosphatase activity and its regulation as shown in our preliminary data is almost certainly of more general importance to established hypertrophy- and failure-related disease mecha- nisms, many of which involve phosphorylation-dependent alterations of structural and regulatory pro- teins of the sarcoplasmic reticulum, the myofibril, and the extra-myofilament cytoskeleton. Thus, this work may serve as an example to help conceptualize the likely mechanistic convergence of a number of heretofore apparently disparate abnormalities of the hypertrophied and failing heart. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the leading cause of hospital admission and readmission in Americans aged 65 or greater. The contractile dysfunction that characterizes systolic heart failure is a maladaptive myo- cardial 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)： 我们在体内分离细胞、分离组织和完整心脏的水平上表明，微管网络密度增加是高壁应力性右或左室肥厚时收缩功能障碍的原因之一。然后，我们发现微管相关蛋白4[MAP4]对微管的亲和力增加是肥大相关的微管网络稳定和致密化的主要决定因素，从而导致收缩功能障碍和基于微管的细胞内运输的相关缺陷，我们也在本背景中描述了这一点。MAP4的磷酸化状态似乎决定了MAP4对微管的亲和力。因此，本申请旨在表征病理性压力超负荷肥厚动物模型中特定部位MAP4磷酸化状态的持续变化，并以生理性容量超负荷肥厚模型作为生长本身影响的对照。然后，我们将通过检测相关的激酶和磷酸酶来描述MAP4磷酸化的调节。我们相信，这项拟议研究的成功实施可能会产生重要的新信息，以帮助理解心脏肥大和衰竭的细胞和分子机制。此外，虽然我们自己感兴趣的终点是微管，但我们初步数据显示的心肌磷酸酶活性及其调节的持续增加几乎肯定对已建立的肥厚和衰竭相关疾病机制具有更普遍的重要性，其中许多涉及肌浆网、肌原纤维和肌丝外细胞骨架的结构和调节蛋白的磷酸化依赖的改变。因此，这项工作可以作为一个例子，帮助概念化一些迄今明显不同的肥厚和衰竭心脏的异常可能的机械会聚。 公共卫生相关性： 在65岁或以上的美国人中，充血性心力衰竭是住院和再次住院的主要原因。以收缩性心力衰竭为特征的收缩功能障碍是一种对几种病理挑战的不适应的心肌反应，包括持续的心脏压力超负荷。这项研究将确定导致衰竭心脏功能障碍的一个重要原因的机制：心肌细胞细胞骨架微管网络的变化。