Remarkable conservation exists between Drosophila and humans at the level of genes and gene functions. For example, there are identifiable fly orthologs for about two-thirds of human disease genes and all of the major signal transduction pathways have been conserved between flies and humans. The availability of RNAi for gene-specific knockdown of mRNA levels has accelerated the pace at which we can undertake the type of molecular genetic analyses that make Drosophila such a powerful system. However, despite the impressive set of tools currently available, locating and/or generating Drosophila disease models can be time consuming, and in most cases, well-characterized loss-of-function alleles or validated RNAi strains are not available. The proposed project would build upon our existing expertise and infrastructure to produce a large collection of in vivo Drosophila RNAi models of human disease, the HuDis-TRiP Resource of Disease Models. This resource will be unique in its large scale, targeting approximately 900 Drosophila orthologs of human disease genes, and in the high level of quality control applied to each RNAi fly stock. For human disease genes for which loss-of-function of the gene is associated with disease state, HuDis-TRiP fly stocks are likely to serve as disease models by mimicking the human disease state at the cell, tissue and/or organism level. Specifically, we propose to:
Aim 1, compile a prioritized list of human disease genes using the Online Mendelian Inheritance in Man database and a community nomination process;
Aim 2, identify 900 high-confidence fly orthologs of these genes;make two transgenic Drosophila RNAi fly stocks per gene;perform phenotypic characterization, quantitative PCR and rescue to validate the resource;
and Aim 3, further characterize the most promising models. Notably, our initial list of conserved disease-associated genes includes genes relevant to nearly all NIH Institutes. In keeping with our commitment to community-based efforts, all RNAi fly stocks will be rapidly transferred to a public stock center and all datasets will be made available through our own database, website (www.flyrnai.org) and other databases. We anticipate that this resource will be widely used by the community, as it will allow scientists to immediately begin their studies with high quality, validated disease models in a powerful genetic system.
(proposed by applicant): The proposed project will generate a large number of animal models of human diseases using the fruit fly Drosophila, which shows remarkable similarity to humans at the level of genes and gene functions. These fly models will provide a cost-effective tool facilitating innovative molecular and genetic studies relevant to a wide variety of diseases and nearly all NIH Institutes.
| Okamoto, Naoki; Viswanatha, Raghuvir; Bittar, Riyan et al. (2018) A Membrane Transporter Is Required for Steroid Hormone Uptake in Drosophila. Dev Cell 47:294-305.e7 |
| Hu, Yanhui; Comjean, Aram; Mohr, Stephanie E et al. (2017) Gene2Function: An Integrated Online Resource for Gene Function Discovery. G3 (Bethesda) 7:2855-2858 |
| Hu, Yanhui; Comjean, Aram; Perrimon, Norbert et al. (2017) The Drosophila Gene Expression Tool (DGET) for expression analyses. BMC Bioinformatics 18:98 |
| Hu, Yanhui; Comjean, Aram; Roesel, Charles et al. (2017) FlyRNAi.org-the database of the Drosophila RNAi screening center and transgenic RNAi project: 2017 update. Nucleic Acids Res 45:D672-D678 |
| Wang, Julia; Al-Ouran, Rami; Hu, Yanhui et al. (2017) MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome. Am J Hum Genet 100:843-853 |
| Mohr, Stephanie E; Hu, Yanhui; Ewen-Campen, Benjamin et al. (2016) CRISPR guide RNA design for research applications. FEBS J 283:3232-8 |
| Hu, Yanhui; Comjean, Aram; Perkins, Lizabeth A et al. (2015) GLAD: an Online Database of Gene List Annotation for Drosophila. J Genomics 3:75-81 |
| Perkins, Lizabeth A; Holderbaum, Laura; Tao, Rong et al. (2015) The Transgenic RNAi Project at Harvard Medical School: Resources and Validation. Genetics 201:843-52 |
| Mohr, Stephanie E; Hu, Yanhui; Kim, Kevin et al. (2014) Resources for functional genomics studies in Drosophila melanogaster. Genetics 197:1-18 |
| Mohr, Stephanie E (2014) RNAi screening in Drosophila cells and in vivo. Methods 68:82-8 |
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