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

Research project

Description

? 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.
StatusActive
Effective start/end date4/1/153/31/19

Funding

  • National Institutes of Health: $449,956.00
  • National Institutes of Health: $442,421.00

Fingerprint

Dilated Cardiomyopathy
Actin Cytoskeleton
Cardiac Myocytes
Knockout Mice
Ventricular Dysfunction
Peptide Elongation Factors
Microfilament Proteins
Striated Muscle
Cardiomyopathies
Transgenic Mice
Actins
Mammals
Myocardium
Biomarkers
Parturition
Muscles

Keywords

  • Medicine(all)