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Flies as a model for the study of human disease

Flies as a model for the study of human disease. Rapid construction of transgenic models of human disease. Well established easy systems to drive knockdown/knockout or over expression of gene expression in tissue or temporal specific patterns.

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Flies as a model for the study of human disease

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  1. Flies as a model for the study of human disease Rapid construction of transgenic models of human disease Well established easy systems to drive knockdown/knockout or over expression of gene expression in tissue or temporal specific patterns Rapid forward genetics – isolate mutants through transposons or chemical mutagenesis Rapid determination of the molecular basis of disease mechanisms Able to rapidly identify modifier/bypass gene pathways via genetic screens for enhancers or suppressors of phenotypes Easy to culture cell lines – very-easy to dsRNA treat genes of interest

  2. The fly GAL4/UAS binary transgenic expression system X OFF Tissue specific promoter GAL4 UAS Transgene • GAL4 is a transcriptional activator protein from yeast • The upstream activating sequence is the GAL4 target ON Tissue specific promoter GAL4 UAS Transgene The progeny of this mating will express the • transgene in cells also expressing GAL4

  3. The life cycle of a fly Adult Pupa White (early) pupa L3 L2 L1 Larva (juvenile) 24 hrs Egg

  4. Drosophila has 4 chromosomes H. sapiens chromosomes

  5. Embryonic Brain Development Hartenstein - Atlas of Drosophila Development (1993) Cold Spring Harbour Laboratory Press

  6. Larval/Pupal Brain Development Hartenstein - Atlas of Drosophila Development (1993) Cold Spring Harbour Laboratory Press

  7. The fly fat body is analogues to adipose tissue, the liver and the haematopoietic system in mammals. Hotamisilgil (2006) Inflammation and metabolic disorders Nature 444, 860-867

  8. Drosophila oenocytes are analogous to mammalian hepatocytes Leopold & Perrimon(2007) Drosophila and the genetics of the internal milieu Nature 450, 186-188

  9. Testing drug candidates in flies Throughput Pandley and Nichols (2011) Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery Pharmacological Reviews 63(2)411-436

  10. ‘Humanized” fly Pex1 mutations

  11. ‘Humanized” fly Pex1 mutations

  12. A ‘visible’ screen for peroxisome function in Drosophila eyes ey – eyeless:GAL4 GMR– Glass Multiple Reporter:GAL4

  13. Drosophila Pex1 is expressed throughout development Pex1 *RNAseq

  14. Drosophila Pex1 is expressed in multiple tissues Pex1 *microarray

  15. Drosophila Pex3 is expressed in multiple tissues Pex3 *microarray

  16. Drosophila Pex7 is expressed highly in the CNS Pex7 *microarray

  17. Drosophila Pex1

  18. Genome wide analysis of Pex1 loss

  19. Genome wide analysis of Pex1 loss

  20. Genome wide analysis of Pex1 loss

  21. Genome wide analysis of Pex1 loss

  22. Loss of Pex1 in flies causes larval lethality

  23. Loss of Pex1 in flies causes a poor growth phenotype

  24. Pex1 mutations do not affect fly musculature

  25. Loss of Pex1 in flies causes a poor growth phenotype

  26. Loss of Pex1 in flies causes severe effects on the Drosophila nervous system

  27. Loss of Pex1 in flies causes severe effects on the Drosophila nervous system

  28. Loss of Pex1 in flies causes severe effects on the Drosophila nervous system

  29. High Throughput screening dsRNA library covering 96% of the Drosophila genome High throughput screening

  30. Studying Peroxisomes in cultured fly cells

  31. Acknowledgements U of Alberta • Simmonds Laboratory • Jing Li • Julie Haskins • Alana Pay • Rachubinski Laboratory • Jenny Chang • Fred Mast • Robert Tower • Rick Porier • Dr. Sarah Hughes McGill Univeristy • Dr. Nancy Braverman

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