Abstract
Many of the discoveries from the rapidly expanding genomic sciences are not effectively utilized in medicine, agriculture and industry. This is partly because of the disconnection between scientists in different disciplines, and because much of the translational research done in both industry and academia is patent-protected and not published in a timely manner. This INCT proposal addresses both these challenges. Firstly, by creating a highly integrated network of researchers in different disciplines: genetics, protein biochemistry, medicinal chemistry, cell- and developmental biology; and second, by committing to open- access research: all data and reagents will be made available to all without restrictions. The INCT aims to unlock the potential of genes relevant for medicine by focusing on the proteins encoded by these genes, and developing a package of tools that enable research on these proteins. The package of research tools might indude expression dones, protein purification protocols, antibodies, crystal structure and a chemical inhibitor. These target-enabling packages (TEPs) will provide the research community with a mechanism to greatly expand their capabilities. To ensure that Brazilian scientists benefit from these tools, our INCT is committing to make them available with no strings attached to all interested researchers. Our INCT is focusing on enabling protein research because protein research is often the “missing link" between genetics and biological functional studies. The proteins encoded by common and mutant disease-related genes, or proteins that are targets for anti- parasitic drugs are often not studied because reagents and tools are not available. Our INCT will overcome this major hurdle to translational science. The INCT will be organized around a core laboratory in UNICAMP, in collaboration with the Structural Genomics Consortium (SGC; www.thesgc.org) (SGC-UNICAMP) and its laboratories at the University of Oxford (SGC-Oxford) and the University of Toronto (SGC-Toronto). Collaborating groups within the INCT network will nominate a list of target genes, based on their research interest. The INCT Core group will done and purify, crystallize and determine the atomic structures of the encoded proteins. Then, the Core and groups within the network will collaborate to develop functional assays for the activity of each protein (e.g. enzymatic, ligand-binding or protein-binding), aiming to understand the function of the proteins. The core lab will optimize the assays for small-molecule screens, and will perform such screens to find chemical starting points for inhibitor development, and will develop chemical probes in collaboration with INCT network scientists in academia and industry. The knowledge and reagents generated from the protein-Ievel studies will be used to formulate and test hypotheses in the relevant cellular and physiological contexts. The key deliverables of the INCT are 15 "Target Enabling Packages" (TEPs), which consist of clones and methods for protein purification, crystallization and activity assays; chemical probes for use modulators of human cell function; and further information on the proteomics, the impact of mutations, and the physiology of the target proteins. TEPs will be utilized promptly by the INCT partners but it will also be published on the INCT web site and in scientific journals, with a mechanism for distribution of the clones and reagents without restrictions on use. Our INCT will collaborate not only with network scientists, but also with any laboratory in Brazil that can suggest new and important targets for research. Ali nominated targets will be prioritized by the INCT management committee. The nominating labs will then be able to use the expertise and infrastructure within the INCT to generate the proteins and initiate structural or functional studies. Each project will be evaluated on an ongoing basis and, where appropriate, developed into full-scale projects or stopped. Ali nominating groups must agree to the release of data and reagents upon completion of the projects. Once projects are accepted, chemical probe-generating collaborations will be initiated in INCT laboratories, in an open collaboration with SGC and industry partners. One innovative action of this INCT is the inclusion of nominations from and plant science. For example, key plant targets, mostly protein kinases, potentially associated to plant response to abiotic stress will enter the Centre pipeline for TEPs development. The chemical probes developed for these proteins will be used to ask questions related to plant response to abiotic stress. These tools will be made available to plant science community without restrictions. In summary, this INCT proposes to create a tightly coordinated network of research groups, in collaboration with the highly successful international Structural Genomics Consortium, to promote the utilization of genetic discoveries for medicinal, plant and industrial development. (AU)
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