Cathy Shanahan
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    Citations

Personal profile

Research interests

We are interested in the molecular regulation of vascular smooth muscle cell (VSMC) phenotype and how it relates to vascular dysfunction in diseases such as atherosclerosis, diabetes, hypertension, chronic renal failure and ageing. Our studies have demonstrated that human VSMCs undergo a phenotypic transition when cultured in vitro. In culture, fully contractile human VSMCs convert into a pan-mesenchymal cell with the capacity to express multiple lineage markers of smooth muscle, osteoblasts, chondrocytes and adipocytes. In particular we are interested in the TGFb-superfamily of morphogens and how they regulate this VSMC plasticity. We hypothesize that similar phenotypic changes occur in vivo in the atherosclerotic plaque and during ageing and these modified, dysfunctional VSMCs contribute to vascular calcification and lipid accumulation and may apoptose or undergo cellular senescence.

A major area of interest is in the regulation of vascular calcification, a detrimental process that occurs in the vessel media and in the atherosclerotic plaque. Our studies on vascular calcification in the context of atherosclerosis, diabetes and chronic renal failure have shown that it is a regulated process similar to bone formation. VSMCs in the normal artery wall constitutively express potent inhibitors of calcification, such as matrix Gla protein (MGP), whose absence results in spontaneous medial calcification. In atherosclerotic calcification and diabetic Monckebergs Sclerosis, expression of inhibitors is reduced and VSMCs express markers of both osteoblast (alkaline phosphatase, bone sialoprotein and osteocalcin) and chondrocyte (collagen II) differentiation. Human VSMCs in culture spontaneously convert to an osteo/chondrocytic phenotype, express the obligate bone transcription factor Cbfa1 and form calcified nodules. Calcification is initiated in nodules by release of apoptotic bodies (AB) and matrix vesicle (MV) like structures from VSMCs that act as a nidus for hydroxyapatite nucleation. In addition, circulating proteins present in serum have also been identified as potent inhibitors of calcification and our studies are aimed at determining the pathological processes that accelerate VSMC phenotypic change and subsequent calcification. We are particularly interested in the role of matrix vesicles in acting as the initial nidus for VSMC calcification.

More recently, in a search for VSMC differentiation markers we identified a novel family of proteins called nesprins. These proteins are type II integral membrane proteins composed of multiple spectrin repeats with N-terminal paired calponin homology domains. They were originally identified a proteins of the inner nuclear membrane however they are also present in multiple cytoplasmic compartments including the ER, SR of the muscle sarcomere, Golgi and mitochondria. These proteins bind emerin and lamin and may play a role in a complex of diseases called laminopathies that include musclular dystrophies, cardiomyopathies, lipodystrophies and progeria syndromes. Nesprins may also function as linker proteins important for subcellular compartmentalization of organelles particularly in skeletal, smooth and cardiac muscle. Our studies are focussing on the role of these proteins in cardiovascular cell functions including the cell cycle, cell migration, cell ageing and nuclear and cytoplasmic signalling pathways.

Research interests (short)

Vascular smooth muscle cell biology; atherosclerosis, vascular calcification; nuclear envelope; nesprins; ageing

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

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