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Background
The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex spans the nuclear envelope and enables force transmission from the cytoskeleton to the nucleus. Lamins are intermediate filament proteins that form the nuclear lamina which protect DNA from these transmitted forces. In a disease state, the LMNA mutation causes deletion or structural alteration of lamins A/C, which reduces the functionality of the nuclear lamina and increases the risk of nuclear rupture. These defects give rise to diseases such as dilated cardiomyopathy in cardiac tissue and muscular dystrophy in skeletal muscle.
LINC complex disruption is a promising therapy for these diseases because it mechanically decouples the nucleus from the cytoskeleton. Although the nucleus remains structurally compromised due to defective lamins A/C, reduced force transmission lowers the risk of nuclear rupture.
Graphic explaining the rationale of LINC complex disruption as a potential treatment for laminopathies.
Motivation
LINC complex disruption is achieved by expressing a dominant negative protein (dnKASH) that competitively blocks the interaction of native LINC complex proteins within the nuclear envelope. Although this strategy has shown efficacy without pathology in sedentary mouse models, its performance under more physiologically demanding conditions remains unknown.
Introducing dnKASH disrupts the binding between native KASH- and SUN-domain proteins in the nuclear envelope, competitively inhibiting the formation of the LINC complex. This strategy has shown efficacy in sedentary mouse models but its performance in more physiologically demanding conditions is unknown.a
Aim
Evaluate the safety and efficacy of LINC complex disruption in physiologically demanding conditions.
Hypothesis
LINC complex disruption will remain safe and effective in mitigating laminopathy in physiologically demanding conditions.
Pregnancy Study
Pregnancy induces physiological, reversible cardiac hypertrophy due to volume overload, hormonal changes, and ECM remodeling. In this study, we aim to analyze echocardiogram data to determine whether wildtype mice and mice expressing the dominant negative protein exhibit different cardiac responses to pregnancy.
Echocardiogram data analysis. Outlining boundaries of the left ventricle walls gives insights to key parameters such as cardiac output, ejection fraction, stroke volume, and left ventricle mass.
Voluntary Exercise
Having intact muscle satellite cells is associated with improved running performance (faster speed and longer distance) in mice. In this study, we aim to determine whether expressing the dominant negative protein affects running performance compared to wildtype mice.
Involuntary Exercise
Involuntary exercise models are also used to assess muscle function. The hanging wire test measures the ability to sustain sufficient tension required to remain suspended in an upside-down position, while the grip strength test measures maximal pulling tension when resisting an external force. In this study, we aim to compare performance between wildtype mice and mice expressing the dominant negative protein, as well as determine whether LINC complex disruption can rescue muscle function of diseased mice with muscular dystrophy.
Future Directions
Results are preliminary at this stage, with additional data to be collected in the spring to determine whether clear distinctions between groups emerge across the three experimental models.
Figure Reference
a. Méjat, A., & Misteli, T. (2010). LINC complexes in health and disease. Nucleus (Austin, Tex.), 1(1), 40–52. https://doi.org/10.4161/nucl.1.1.10530.
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