More than one-third of all cases of dilated cardiomyopathy are caused by inherited mutations, with 5% to 10% of these mutations being linked to the LMNA gene, which encodes the nuclear envelope proteins lamin A and C. Importantly, mutations in the LMNA gene are also responsible for a broad spectrum of other diseases, including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy and familial partial lipodystrophy. Despite recent advances, the mechanism(s) responsible for the often muscle-specific defects caused by different lamin mutations remains elusive. The central hypothesis of this proposal is that lamin mutations can cause skeletal and cardiac muscle disease through two, possibly overlapping mechanisms: (i) loss of structural function of lamins A and C, leading to rupture of the more fragile nucleus in mechanically stressed tissues; (ii) disturbing (mechanosensitive) signaling pathways that results in impaired function of muscle cells. Specific LMNA mutations may differentially affect these distinct aspects of lamin function, resulting in a broad spectrum of disease phenotypes. My long term goal is to understand the molecular mechanism(s) by which mutations in the nearly ubiquitously expressed lamins can lead to muscle-specific phenotypes and to explore to what extent impaired nuclear structure and altered cellular sensitivity to mechanical stress contribute to the muscle-specific phenotypes. In the first aim, we will test the hypothesis that altered nuclear mechanics result in increased nuclear rupture in mechanically stressed tissue. By using a genetic reporter assay that can detect even transiently compromised nuclear envelope integrity in cardiac myocytes in three mouse models of muscular laminopathies, we can directly assess whether mutations in nuclear envelope proteins cause increased rates of nuclear rupture in cardiac tissue. In the second aim, we will determine the relationship between impaired nuclear mechanics and the severity of muscular phenotypes in laminopathies. Using drosophila melanogaster models expressing a panel of lamin mutations with variable muscle involvement, we will relate effects of the mutations on the mechanical properties of nuclei in intact muscle tissue in drosophila larvae with the severity of muscle defects in adult flies. In the third aim, we will investigate the interplay between lamin mutations responsible for dilated cardiomyopathy and a specific signaling pathway, myocardin-related transcription factor A (MRTF-A). We will explore the mechanism(s) responsible for the impaired nuclear translocation of MRTF-A in lamin A/C-deficient and mutant cells we recently discovered and assess the functional consequences of impaired MRTF-A signaling on cellular function. Studying the effects of lamin mutations on nuclear structure and cellular signaling will improve our understanding of normal and tissue-specific functions of these proteins and lead to new insights into the molecular mechanisms responsible for dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy and other laminopathies, potentially providing new targets for the treatment of these diseases.

Public Health Relevance

Heart disease and muscular dystrophies, characterized by progressive wasting of muscles in the arms, legs, and trunk of patients, are often caused by inherited mutations in specific genes. Our studies will address the disease mechanism by which mutations in a particular gene cause these muscle-specific defects and may also lead to new insights into the normal function of the proteins encoded by the mutated gene. A better understanding of how these mutations can alter the structure and function of muscle cells and impair critical signaling pathways could open the door for pharmacological approaches to normalize these pathways, potentially leading to new clinical treatments for patients affected by these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL082792-10
Application #
9067464
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2007-01-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cornell University
Department
Type
Organized Research Units
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Elacqua, Joshua J; McGregor, Alexandra L; Lammerding, Jan (2018) Automated analysis of cell migration and nuclear envelope rupture in confined environments. PLoS One 13:e0195664
Yadav, Sandeep Kumar; Feigelson, Sara W; Roncato, Francesco et al. (2018) Frontline Science: Elevated nuclear lamin A is permissive for granulocyte transendothelial migration but not for motility through collagen I barriers. J Leukoc Biol 104:239-251
Kirby, Tyler J; Lammerding, Jan (2018) Emerging views of the nucleus as a cellular mechanosensor. Nat Cell Biol 20:373-381
Bakhoum, Samuel F; Ngo, Bryan; Laughney, Ashley M et al. (2018) Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553:467-472
Singh, Ankur; Brito, Ilana; Lammerding, Jan (2018) Beyond Tissue Stiffness and Bioadhesivity: Advanced Biomaterials to Model Tumor Microenvironments and Drug Resistance. Trends Cancer 4:281-291
Shah, Pragya; Wolf, Katarina; Lammerding, Jan (2017) Bursting the Bubble - Nuclear Envelope Rupture as a Path to Genomic Instability? Trends Cell Biol 27:546-555
Mekhdjian, Armen H; Kai, FuiBoon; Rubashkin, Matthew G et al. (2017) Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix. Mol Biol Cell 28:1467-1488
Isermann, Philipp; Lammerding, Jan (2017) Consequences of a tight squeeze: Nuclear envelope rupture and repair. Nucleus 8:268-274
Morelli, Federica F; Verbeek, Dineke S; Bertacchini, Jessika et al. (2017) Aberrant Compartment Formation by HSPB2 Mislocalizes Lamin A and Compromises Nuclear Integrity and Function. Cell Rep 20:2100-2115
Lammerding, Jan; Wolf, Katarina (2016) Nuclear envelope rupture: Actin fibers are putting the squeeze on the nucleus. J Cell Biol 215:5-8

Showing the most recent 10 out of 57 publications