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Our group`s research focuses on the molecular and cell biology of lipid activated transcription factors, so called nuclear receptors. Nuclear hormone receptors are ligand activated transcription factors participating in the regulation of cellular proliferation, differentiation and homeostasis. Members of this receptor superfamily, such as the estrogen receptor, progesterone receptor or the retinoic acid and thyroid hormone receptor are classical endocrine regulators.

The ligand-induced switch

We are interested in the molecular details of hormone action. Lipid soluble hormones such as oestrogens and retinoids act via small protein molecules (receptors)which bind to and regulate the expression of certain genes. This is how they affect the function and fate of cells and tissues. To positively or negatively regulate gene expression they need to communicate with other protein molecules. The specific protein molecules interacting with the receptors were recently identified. It is critical to understand how the small lipid soluble molecules (hormones) regulate these interactions. We try to understand the details and molecular determinants of these interactions using molecular and cell biological approaches.

We are interested in uncovering how lipid metabolism and signaling is linked to regulation of immune function at the cellular level. Our hypothesis is that the nuclear receptors: Peroxisome Proliferator Activated Receptor gamma (PPARg), Retinoic Acid Receptor (RAR) and Vitamin D Receptor (VDR) form an interrelated network and regulate immune function in dendritic cells and macrophages providing the cells with a mechanism to detect changes in the intra- and extracellular lipid environment and reprogram itself. More specifically, we would like to know what are the signals and how are they generated, which genes and gene networks are controlled and how it is effecting immune function.

The links between lipid metabolism lipid, signaling and immune function are not well understood. Our work has provided some new insights and led to novel concepts on how nuclear receptors might link these two seemingly distant fields (lipid metabolism and immune function) at the cellular level. The models of our studies are the dendritic cells, a key cell type serving as a sentinel of the immune system and also macrophages. In the body there are several tissue compartments where dendritic cells are likely to be exposed to large amounts of lipids. These include the gut- associated lymphoid tissue (GALT), in the small intestine the lamina propria is important to maintain peripheral tolerance, dendritic cells can also be found in atherosclerotic plaques. It would be important to understand how increased extra- and intracellular lipids contribute to dendritic cell subtype specification and alterations in their immune function. Our studies have been aimed at unraveling the contribution of PPARg, RAR and VDR to these responses. We have systematically mapped the transcriptional changes associated with the activation of these transcription factors using global gene expression profiling and also followed up some of the leads and linked PPARg activation to lipid antigen presentation and retinoid biosynthesis. We also connected VDR induced transcriptional changes to the development of immune tolerance. These studies strengthened the argument that this group of transcription factors also represents a gateway to manipulating dendritic cells and also macrophages for therapeutic use in advanced cell therapy or in inflammatory diseases.