ROLinMAP

Vitamin A (retinol) is a micronutrient critical for normal development and physiology in vertebrates. Both vitamin A deficiency or excessive exposure to retinoids (i.e., natural and synthetic analogues of retinol and its metabolites) are threats to human health and are either causal factors or contribute to the physiopathology of a large number of diseases. The very diverse functions of vitamin A require highly regulated and multilevel control of its availability, metabolism, and signaling. Although these processes have been widely studied, the existing knowledge does not allow their full understanding. In addition, this knowledge is mostly limited to few organs or tissues including liver, eye or adipose tissue, with relatively little data available on adult brain and neuronal tissue. Such data might be, however, particularly relevant for understanding the physiopathology of neurodegenerative diseases like Huntington’s or Parkinson’s disease, or neurological and psychiatric symptoms associated with chronic alcohol intake, all of which were associated with deficient retinoid signaling in distinct brain regions. The overreaching aim of this project is to better understand the molecular basis of retinoid metabolism and signaling, including their storage and transport in physiological and pathological conditions, focusing primarily on (but not limiting to) brain and neural tissue. Specifically, we propose to develop new methods to study retinoid signaling which should address some unmet questions including diversity of bioactive retinoids, their structure, molecular and biological specificity, and cellular and subcellular distribution. To this end, we will first synthesize retinoids carrying a biologically inert azide group making them amenable for click-chemistry reactions with chemical probes. Such probes will be designed, synthetized and validated for different applications. In particular they should allow highly sensitive detection and capture of low-abundance or difficult-to-detect retinol metabolites and unprecedented optical imaging of retinoid distribution at cellular and subcellular levels, as well as determination of retinoid-interacting proteins related to their storage, mobility and actions. Analyses of dedicated cellular and animal models throughout this project should link retinoid diversity with pleiotropic activities of vitamin A in animal physiology and pathology. By combining already established and novel in vitro and in vivo experimental models and approaches for studying retinoid signaling in the context of brain disease, these technologies should expand the current knowledge on vitamin A metabolic pathways, with the identification of new metabolites and proteins relevant for these pathways, which will help deciphering the complex functions of retinoids in control of cell proliferation, differentiation and function. New metabolites might also be of direct relevance for diagnostics or treatment of selected CNS disorders. Importantly, the project will provide a proof of concept for a new strategy of integrative analyses of biological processes, which could be applied virtually to any type of biomolecules.