The role of the nuclear envelope proteins in cardiovascular ageing
Research type
Research Study
Full title
The role of the nuclear envelope proteins and nuclear lamina in cardiovascular ageing
IRAS ID
143408
Contact name
Cathy Shanahan
Contact email
Sponsor organisation
King's College London
Research summary
The muscle cells in the heart and vessel wall have multiple functions in regulating heart contraction/excitation, blood flow and vessel repair. However, as we age, our heart and vessel cells become susceptible to environmental insult and diseased, leading to weakening of the heart and vessel walls and may eventually lead to a heart attack or stroke. We are interested in determining the signals and pathways that lead to muscle cell dysfunction and ageing by investigating the disease process and also the function of novel proteins that may contribute to premature ageing.
Lamin A/C are components of the nuclear lamina and critical for nuclear organisation and function. Mutations in the lamin A/C gene lead to laminopathies manifesting with multiple cardiovascular phenotypes including Emery-Dreifuss muscular dystrophy (EDMD) and dilated cardiomyopathy (DCM) and atherosclerosis. Mutations in nesprin-1, a novel lamin A/C binding partner at the nuclear envelope (NE), also cause EDMD and DCM. Therefore, we hypothesize mutations in the NE proteins will increase NE fragility and cause disruption of mechanical connections between the plasma membrane and the nucleus as well as the essential regions associated with contraction/excitation and vessel tone of muscle cells when exposed to mechanical strain, leading to defects in mechanotransduction and myogenesis.
In this project, our lab propose to study the role of the NE proteins in regulating normal, pathological and aging processes in the heart and blood vessels by employing immunofluorescence and immunohistochemistry techniques. We will determine if mutations identified in DCM and EDMD patients cause disruption of the NE and compromise the myofilament network, and whether changes in these proteins are associated with normal ageing. Therefore, we will study control and patient tissue samples obtained from biobanks.
These studies will further our understanding of the roles of nuclear envelope proteins in cardiac muscle cells, and may reveal novel pathways that contribute to the development of cardiac cell dysfunction, cardiomyopathy and premature cardiovascular ageing.
REC name
London - City & East Research Ethics Committee
REC reference
13/LO/1950
Date of REC Opinion
20 Mar 2014
REC opinion
Further Information Favourable Opinion