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Identification of proteins responsible for iodide capture in the thyroid gland – ChemBiode

Identification of proteins responsible for iodide capture in the thyroid gland

The capture of iodide into thyroid follicular cells is essential for the biosynthesis of thyroid hormones. It is now well-established that iodide uptake is impaired in many diseases such as cancer (thyroid, breast, lung, intestine, pancreas…), autoimmune disease, hyper- and hypothyroidism. Moreover, in case of exposure to radioactive iodine species, toxic radioiodide is efficiently taken up by the thyroid gland leading to deleterious effects.

Aim: Identify proteins responsible for iodide capture in the thyroid gland

Although many efforts have been made to characterize the mechanism of iodide transport and its regulation at a cellular level, only very little is known. This project aims at dissecting the cellular pathways implicated in the capture of iodide in thyroid cells.Such a discovery will open promising perspectives for the development of new drugs and/or therapeutic solutions in many thyroid and extra-thyroid diseases. <br />This project uses an original and multidisplinary approach to answer a fundamental biological issue. <br />

Using a phenotypic screen, we have identified the first small molecules inhibitors of iodide uptake in thyroid follicular cells. The present project aims at finding the molecular targets of each of these inhibitors using a strategy called chemical proteomics. The inhibitors will be derivatized into pharmacological tools designed to isolate their respective targets. The strategy is based on an affinity-based fishing approach, followed by functional validation of the targets by knock-down and/or over-expression.

Under the supervision of the coordinator (Yves Ambroise, partner 1), the project started April 1st 2013 by the recruitment of a postdoctoral fellow (Clarisse Lejeune, partner 1) in charge of the design/synthesis of chemical probes (tasks 2 and 3) as well as of their biological evaluation (task 3) and of purification/identification of the target proteins (tasks 4, 5, 6 and 7). At the SCBM laboratories, the postdoctoral fellow carried out the synthesis of the chemical probes by using standard methods of organic and analytical chemistry. The design of the chemical probes was accomplished based on SAR studies previously reported for the three different chemical libraries and literature precedents. At the same time, the postdoctoral fellow (partner 1) was trained by the coordinator (partner 1) and the biologist co-worker (François Leteutre, partner 3) to cellular and biochemical techniques in order to proceed to FRTL-5 cells growth needed for biological tests and the identification of proteins (SDS-PAGE). In parallel, partner 3 started preliminary transfection experiments on FRTL5 in order to set up protocols for task 8.

An iodide transport assay is going to be carrying out on the three different chemical probes, previously synthesized at the SCBM laboratory. Once tested and radiolabelled, the chemical probes will be illuminated by using a photolysis UV lamp (the system has been purchased and received) in order to form a covalent bond between the target protein and the chemical probe. The collaboration with the bioanalyst partner 2 (François Fenaille) will start once the target protein purification is done.

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The capture of iodide into thyroid follicular cells is essential for the biosynthesis of thyroid hormones. Iodide uptake is impaired in many diseases such as cancer (thyroid, breast, lung, intestine…), autoimmune disease, hyper- and hypothyroidism, revealing the key role of iodide in many health conditions. Moreover, in case of exposure to radioactive iodine species (nuclear accident, nuclear workers), toxic radioiodide is efficiently taken up by the thyroid gland leading to deleterious effects. Solutions for body decontamination are still awaited. Although many efforts have been made to characterize the mechanism of iodide transport and its regulation at a cellular level, only very little is known. Recently, from a phenotypic screening we have identified the first small molecules inhibitors of iodide uptake in thyroid follicular cells. The present project aims at finding the molecular targets of each of these inhibitors using a strategy called chemical proteomics. The inhibitors will be derivatized into pharmacological tools designed to isolate their respective targets. Such a discovery will open promising perspectives for the development of new drugs and/or therapeutic solutions in many thyroid and extra-thyroid diseases. This project uses an original and multidisplinary approach to answer a fundamental biological issue. Preliminary experiments in our lab have permitted to isolate a specific target, showing the feasibility of our approach by our consortium.

Project coordinator

Monsieur AMBROISE Yves (Laboratoire public)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CEA-DSV-iBiTecS Commissariat à l'énergie atomique-Direction des sciences du vivant-Institut de biologie et de technologie de Saclay-Service de Biologie intégrative et génétique moléculaire
CEA-DSV-iBiTecS Commissariat à l'énergie atomique-Direction des sciences du vivant-Institut de biologie et de technologie de Saclay-Service de pharmacologie et d'immunoanalyse

Help of the ANR 386,934 euros
Beginning and duration of the scientific project: February 2013 - 36 Months

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