MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY

MAP4 心脏微管网络密度的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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右心室或左心室肥厚中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微管网络稳定和致密化的主要决定因素，从而导致微管收缩功能障碍和相关缺陷。基于细胞内的运输，我们也在这种情况下进行了描述。 MAP4 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大动物模型中位点特异性 MAP4 磷酸化状态的持续变化，并用生理容量超负荷肥大的平行模型作为生长本身任何影响的对照。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。我们相信，所提出的研究的成功执行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，但我们的初步数据显示的心脏磷酸酶活性的持续增加及其调节几乎肯定对已建立的肥大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性改变。因此，这项工作可以作为一个例子，帮助概念化迄今为止许多明显不同的肥厚和衰竭心脏异常可能的机械收敛。公共卫生相关性：充血性心力衰竭是 65 岁或以上美国人入院和再入院的主要原因。收缩性心力衰竭特征的收缩功能障碍是心肌对多种病理挑战（包括持续心脏压力超负荷）的适应不良反应。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：心肌细胞细胞骨架的微管网络的改变。