Deciphering the role of Lmod2 in thin filament length regulation and dilated cardiomyopathy

解读 Lmod2 在细丝长度调节和扩张型心肌病中的作用

基本信息

批准号：
9039137
负责人：
Carol C Gregorio
金额：
$ 44.24万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039137
关键词：
Actin-Binding Protein Actins Architecture Biological Markers Birth Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies Complex Data Defect Dilated Cardiomyopathy Disease Disease Progression Early Diagnosis Elongation Factor Exhibits Family member Filament Functional disorder Genetic Models Goals Health Heart Heart Abnormalities Human Knock-out Knockout Mice Laboratories Lead Length Link Mammalian Cell Mammals Measures Microfilaments Minus End of the Actin Filament Mus Muscle Muscle Cells Muscle Development Muscle function Myocardium Phosphorylation Play Protein Array Proteins Regulation Role Sampling Striated Muscles Structural defect Structure Thick Filament Thin Filament Tissues Transduction Gene Transgenic Mice Transgenic Organisms Ventricular Dysfunction Viral Work combinatorial genetic regulatory protein heart function human tissue improved in vivo insight interdisciplinary approach knock-down mouse model multidisciplinary muscle LIM protein new therapeutic target novel novel therapeutics overexpression pre-clinical protein function research study single molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The mechanism whereby cardiomyocytes precisely regulate the assembly of their actin-containing thin filaments at the level of single molecules is still largely unknown. We have discovered that Leiomodin 2 (Lmod2), a striated muscle specific actin-binding protein, functions as the first described actin filament pointed- end elongation factor in mammals. Little is known, however, regarding the function of Lmod2 in the heart. Preliminary analysis of our unique Lmod2 knockout (KO) mice reveal that they die ~3 weeks following birth, with hearts displaying severe contractile dysfunction and ventricular chamber enlargement, consistent with dilated cardiomyopathy (DCM). Strikingly, Lmod2 KO hearts have shorter thin filaments. When we analyzed human heart samples with DCM and hearts from multiple mouse models of DCM we discovered that they too have shorter thin filaments. Remarkably, when DCM was "rescued" in the hearts of a well-studied mouse model of DCM (muscle LIM protein (MLP) knockout mice), proper thin filament lengths were restored. We hypothesize that thin filament length changes are a general mechanism of the complex remodeling that occurs in DCM. The long-term goal of the proposed work is to discover common pathophysiologies of dilated hearts that can be used as therapeutic targets for the treatment of DCM. The immediate goals of this proposal are to determine mechanisms by which actin-thin filament architecture is regulated in cardiac muscle, the role Lmod2 plays in this regulation, and how defects in this regulation contribute to DCM. Using novel transgenic mice (with either abnormally long or short thin filaments), human muscle samples and primary cardiomyocytes, we will take a multidisciplinary approach to accomplish three Specific Aims focused on determining: 1) the effect loss of Lmod2 has on cardiac development and function; 2) the mechanism by which Lmod2 functions to elongate thin filaments; and 3) the role thin filament length dysregulation plays in cardiomyopathies, and whether heart function and remodeling can be rescued if thin filament regulation is restored in a dilated heart in vivo. We predict that completion of this project will result in the discovery of one critical general mechanism and a novel structural biomarker (i.e., thin filament length dysregulation) of the complex remodeling seen in DCM. These discoveries will potentially facilitate early detection of DCM and lead to new therapeutic options.

描述（由申请人证明）：在单分子水平上，将其肌动蛋白含蛋白的蛋白质的组装降低了，我们仍然发现了静脉2（LMOD2）蛋白，首先描述了肌动蛋白丝状触发端口延长延长因子。在哺乳动物中。 DCM我们发现它们也很薄丝。是要发现可以用作DCM触及目标的扩张心脏的Pa thysiologies。使用新型的转基因小鼠，人类肌肉样本和主要心肌细胞的贡献，我们将采用多学科的方法来完成三个针对G的特定目标薄的GTH失调在体内恢复心脏疾病的心脏调节中会恢复。在DCM中。