MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY

MAP4 心脏微管网络密度的调节

• 批准号: 8639216
• 负责人: Donald R. Menick
• 金额: $ 5.72万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639216
• 关键词: Accounting; Acidic Region; Admission activity; Adult; Affinity; Agonist; Alzheimer' s Disease; American; Amino Acid Repetitive Sequences; Amino Acids; Animal Model; 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; Disease; Dissociation; Employee Strikes; Enzymes; Exhibits; Failure; Family; Family Felidae; Fiber; Functional disorder; G-Protein Signaling Pathway; Genes; Glycogen Synthase Kinase 3; Goals; Grant; Growth; Guanosine Triphosphate; Health; Heart; Heart Hypertrophy; Heart failure; Holoenzymes; Hospitals; Human; Hypertrophy; Image; In Vitro; Left Ventricular Hypertrophy; MAP4; Mediating; Microfilaments; Microtubule Depolymerization; Microtubules; Mitogen-Activated Protein Kinases; Mitosis; Mitotic spindle; Modeling; Molecular; Monomeric GTP-Binding Proteins; Muscle; Myocardium; Myofibrils; N-terminal; Neurons; Oranges; Phenotype; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Principal Investigator; Proline; Proline-Rich Domain; Protein Dephosphorylation; Protein Family; Protein Isoforms; Protein Kinase C; Protein phosphatase; Proteins; Pulmonary artery structure; Regulation; Research; Role; Sarcoplasmic Reticulum; Serine; Serine Phosphorylation Site; Signal Transduction; Site; Stress; Structure; Systolic heart failure; Tail; Tandem Repeat Sequences; Tissues; Tubulin; Up-Regulation; Viscosity; Work; aged; base; density; dimer; genetic regulatory protein; in vivo; inhibitor/antagonist; interest; link protein; member; overexpression; p21-activated kinase 1; phosphoinositide-dependent kinase 1; pressure; programs; receptor coupling; response; trafficking; Accounting; Acidic Region; Admission activity; Adult; Affinity; Agonist; Alzheimer' s Disease; American; Amino Acid Repetitive Sequences; Amino Acids; Animal Model; 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; Disease; Dissociation; Employee Strikes; Enzymes; Exhibits; Failure; Family; Family Felidae; Fiber; Functional disorder; G-Protein Signaling Pathway; Genes; Glycogen Synthase Kinase 3; Goals; Grant; Growth; Guanosine Triphosphate; Health; Heart; Heart Hypertrophy; Heart failure; Holoenzymes; Hospitals; Human; Hypertrophy; Image; In Vitro; Left Ventricular Hypertrophy; MAP4; Mediating; Microfilaments; Microtubule Depolymerization; Microtubules; Mitogen-Activated Protein Kinases; Mitosis; Mitotic spindle; Modeling; Molecular; Monomeric GTP-Binding Proteins; Muscle; Myocardium; Myofibrils; N-terminal; Neurons; Oranges; Phenotype; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Principal Investigator; Proline; Proline-Rich Domain; Protein Dephosphorylation; Protein Family; Protein Isoforms; Protein Kinase C; Protein phosphatase; Proteins; Pulmonary artery structure; Regulation; Research; Role; Sarcoplasmic Reticulum; Serine; Serine Phosphorylation Site; Signal Transduction; Site; Stress; Structure; Systolic heart failure; Tail; Tandem Repeat Sequences; Tissues; Tubulin; Up-Regulation; Viscosity; Work; aged; base; density; dimer; genetic regulatory protein; in vivo; inhibitor/antagonist; interest; link protein; member; overexpression; p21-activated kinase 1; phosphoinositide-dependent kinase 1; pressure; programs; receptor coupling; response; 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.

描述（由申请人提供）： 我们已经在分离的细胞，分离的组织和完整的心脏体内显示了微管网络密度增加是高壁应力右或左心室肥大中收缩功能障碍的原因之一。然后，我们表明，微管相关蛋白4 [MAP4]对微管的亲和力是与肥大相关的微管网络网络的主要决定因素，并因此在基于微管内的胞内移植中所描述的是收缩功能障碍和相关性的负责。 MAP4磷酸化状态似乎确定了微管的MAP4亲和力。因此，该应用程序旨在表征病理压力超负荷肥大的动物模型中位点特异性MAP4磷酸化状态的持续变化，其生理体积超负荷肥大的平行模型可作为对生长本质的任何影响的控制。然后，我们将通过检查相关激酶和磷酸酶来描述MAP4磷酸化的调节。我们认为，拟议研究的成功执行可能会产生重要的新信息，以帮助了解心脏超前和失败的细胞和分子机制。此外，虽然我们自身的终点是微管，但心脏磷酸酶活性及其调节的持续增加，如我们的初步数据所示，对于确定的与肥大相关的疾病和失败相关的疾病机构的重要性肯定更为重要，其中许多涉及与磷酸化有关的结构和调节性的依赖性症状及其与磷酸化的危害相关的变化，并且是较重要的。外丝细胞骨架。因此，这项工作可以作为一个例子，以帮助概念化许多迄今为止许多近距离异常异常的机理融合。