Cardiovascular diseases are still a major concern for the global health. The main underlying pathology of this disease is atherosclerosis which is characterized by the accumulation of lipids and... Show moreCardiovascular diseases are still a major concern for the global health. The main underlying pathology of this disease is atherosclerosis which is characterized by the accumulation of lipids and immune cells in the arterial wall leading to a chronic local inflammation and lesion formation. In this thesis, we aimed to (1) validate the use of zebrafish in cholesterol metabolism and atherosclerosis research, (2) study the role of certain classes of scavenger receptors in lipoprotein uptake and cholesterol-based functions, and (3) validated two immune-based potential targets for atherosclerosis. Show less
Drug delivery across the skin is a challenging task because of the skin barrier. The skin barrier underlies in the outermost layer of the skin, the stratum corneum (SC). The lipids play a crucial... Show moreDrug delivery across the skin is a challenging task because of the skin barrier. The skin barrier underlies in the outermost layer of the skin, the stratum corneum (SC). The lipids play a crucial role in this barrier function. The focus of this PhD project was to elucidate the molecular structure of the lipid matrix present in the SC and to relate this structure with the barrier function. The lipid compositions selected for these studies were particularly chosen to understand the changes in barrier function in dry and diseased skin, i.e.,atopic eczema, Netherton syndrome compared to healthy skin. A variety of biophysical and analytical methods such as X-ray diffraction, neutron diffraction, infra-red spectroscopy, microscopy and LC/MS were combined to unravel the molecular structure. Diffusion studies and trans-epidermal water loss measurements were carried out to relate lipid organization with the lipid barrier. All the diffraction studies were performed in Grenoble, France at the ESRF (X-rays) and ILL (neutron). Neutron diffraction studies are in collaboration with King's College, University of London (Prof. J. Lawrence, Dr. D. Barlow). Show less
Current therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify... Show moreCurrent therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify new therapeutic strategies for treating atherosclerosis, it is important to study the interactions between the cells that make up the atherosclerotic lesion. This thesis describes the role of endothelial cells and macrophages during lesion formation, as well as the expression patterns of sterol sensors in vascular smooth muscle cells present in the lesion. These new insights contribute to our understanding of atherosclerosis open up new avenues of atherosclerosis research Show less
Endocytosis can be conceptually broken down into two stages: The formation of the nascent vesicle containing the ingested proteins and lipids, and its subsequent maturation into a degradative... Show moreEndocytosis can be conceptually broken down into two stages: The formation of the nascent vesicle containing the ingested proteins and lipids, and its subsequent maturation into a degradative compartment. During this maturation process proteins can be recycled back to the plasma membrane to prevent degradation. The vesicular membrane and the luminal contents undergo considerable remodeling to transform this compartment into a degradative one. This stops signal transduction by degrading the receptors within the vesicle and also generates antigens for presentation on MHC class II molecules in order to elicit an adaptive immune response. The engulfment of large particles and microorganisms (e.g. pathogens) is referred to as phagocytosis. The vesicle created by phagocytosis is called the phagosome. Phagosome maturation is considered to involve a complex sequence of fusion and fission events with the sub compartments of the endocytic pathway. In many ways, phagosome maturation recapitulates the progression of cargo along the endocytic pathway. In this thesis we have described molecular mechanisms that regulate the endocytic route and how pathogens explore this endocytic route to ensure survival. Show less
