A component of the nuclear substructure, A-type lamins (encoded by LMNA), are targets for mutation in a range of diseases termed laminopathies. The most commonly occurring affect skeletal muscle and cardiac function, with LMNA mutations resulting in muscular dystrophy (EDMD2/3 and LGMD1B) and dilated cardiomyopathy with conduction defects (CMD1A). The molecular mechanisms causing pathology in these diseases are poorly understood. In preliminary studies, we find that tissues from mice lacking A-type lamins exhibit elevated mTOR signaling that contributes to pathology. The fundamental goals of this proposal are to determine the mechanistic links between altered A-type lamin function, elevated mTOR activation and cardiac disease. The central hypothesis is that A-type lamin's function at the nuclear periphery is important for controlling signal transduction pathways that in turn impact mTOR activation.
Aim 1 is devoted to connecting signaling pathways leading from reduced lamin A/C expression to enhanced mTOR signaling, focusing on MAP kinase activation as a potential link. In the second Aim, I describe experimental approaches to determine the consequences of aberrantly elevated mTOR signaling in cardiac and skeletal muscle tissue, focusing on a novel microRNA (miRNA) pathway that we have identified. Lastly, the efficacy of rapamycin in two other mouse models that more closely resemble human pathology will be examined.

Public Health Relevance

LMNA mutations result in over 13 different syndromes, termed laminopathies, resulting in disease phenotypes ranging from muscular dystrophy to accelerated aging, of which there are no effective therapies. The molecular events underlying pathology remain poorly understood and this proposal will derive a molecular understanding of disease progression in mouse models resembling human laminopathies. Importantly, our findings have the potential to extend beyond diseases caused by LMNA mutations to cardiac and possibly skeletal muscle diseases themselves.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM103149-02
Application #
8519121
Study Section
Special Emphasis Panel (ZRG1-F05-R (20))
Program Officer
Janes, Daniel E
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$55,670
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945