Module 5: Regenerative Therapies for Renal Repair

 Module Leader Professor Melissa Little
 Host Organisation University of Queensland

Changes since the launch of the Collaborative Streams have meant that the research of this Module now formally lies outside of Collaborative Stream 3. However, the technology and expertise supporting this research is intertwined and reliant on that incorporated within Collaborative Stream 3.

This research is being funded by the Queensland State Government as a National/International Research Alliance Project with the ASCC. The ASCC does not provide any direct funding for this research as part of the Collaborative Stream. It is aligned with Collaborative Stream 3 via the provision of technology and expertise from Professor Andrew Elefanty, Professor Ed Stanley and Dr Andrew Laslett. hESC culture skills are provided by the Queensland node of the ASCC.

Module description

While the identification of stem cells in the brain raised the hope that as yet unidentified stem cells existed in all organs, it is possible that no such population exists in the kidney or that these can not be harvested from or successfully delivered to end stage renal patients. Here we propose to screen a natural compound library to identify conditions under which human embryonic stem cells can be induced to become renal progenitors. This will benefit the ASCC hES differentiation program as a whole by pioneering the approach of high content natural product screens on hES reporter lines and will directly benefit others interested in mesodermal endpoints given the pilot screen will be performed on the Mixl1-GFP reporter hES cell line, hence identifying compounds able to induce mesendodermal fate.

Aims

  1. To develop the process of high throughput screening of hES cell lines in a 96-well format.
  2. To develop human embryonic stem cell lines which report differentiation into kidney progenitors via the production of fluorescent proteins.
  3. To screen molecular diversity libraries for novel compounds that can drive the development of kidney from human embryonic stem cells.

Module Leader biography

Professor Melissa Little is Group Leader of the Renal Development and Disease Laboratory at the Institute for Molecular Bioscience (IMB), The University of Queensland (UQ). Her research focuses on the molecular genetics of kidney development and the causes of renal disease, with the aim of developing stem cell technology for use in kidney regeneration. She has published over 80 articles in this area. Professor Little established the Renal Regeneration Consortium, a panel of national experts that works towards developing novel strategies for kidney regeneration. A direct outcome of this initiative was the incorporation of Nephrogenix Pty Ltd, which is developing cell-based therapies for renal disease.

Throughout her career, Professor Little’s achievements have been recognised by awards such as the Australian Academy of Sciences Gottschalk Medal in Medical Sciences (2004), the GlaxoSmithKline Award for Research Excellence (2005), and the Smart State Smart Women Award (2006). In 2006, she was awarded a prestigious Eisenhower Fellowship, which recognised her contribution to both the commercial and academic sectors.

Contact details

 E-mail  m.little@imb.uq.edu.au
 Phone   +61 7 3346 2054
 Web  www.imb.uq.edu.au/index.html?page=14032&pid=0

Selected publications

  1. Bickmore, W.A., Oghene, K., Little, M.H., Seawright, A., Van Heyningen, V., Hastie, N.D. Modulation of DNA binding specificity by alternative splicing of the Wilms tumor wt1 gene transcript. Science  (1992) 257,235-237
  2. Little, M.H., Prosser, J., Condie, A., Smith, P.J., Van Heyningen, V., Hastie, N.D. Zinc finger point mutations within the WT1 gene in Wilms' tumor patients. Proc. Natl. Acad. Sci. USA.  (1992) 89, 4791-4795
  3. Little, M.H., Williamson, K.A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N.D., van Heyningen, V. Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Human Molecular Genetics  (1993)  2(3),259-264
  4. Kennedy, D., Ramsdale, T., Mattick, J. and Little, M. An RNA recognition motif in WT1 revealed by structural modelling. Nature Genetics  (1996) 12(3),329-332
  5. Patek, C.E.,  Little, M.H., Fleming, S., Miles, C., Charlieu, J-P., Clarke, A.R., Miyagawa, K., Christie, S., Doig, J., Harrison, D.J., A.J., Porteous, D., Brookes,  Hooper, M.L. & Hastie, N.D. A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc. Natl. Acad. Sci. USA  (1999) 96(6),2931-2936
  6. Challen, GA, Martinez, G, Davis, M, Teasdale, R, Grimmond, S and Little, MH. Identifying the molecular phenotype of renal progenitor cells. (2004) J Am Soc Nephrol.  15(9):2344-57
  7. Challen G, Gardiner B, Caruana G., Martinez G., Davis M., Crowe M., Taylor D., Bertram J, Teasdale RD., Little MH, Grimmond SM. Temporal and spatial transcriptional programs in murine metanephric development. (2005) Physiological Genomics. 23(2):159-71
  8. Challen GA, Ivan Bertoncello I, Deane J, Ricardo S & Little MH. Kidney side population cells represent a non-haematopoietic but heterogeneous population with multilineage and renal potential. (2006) J. Amer. Society Nephrol. 17(7):1896-912.
  9. Brunskill E, Aronow B, Georgas K, Rumballe B, Valerius MT, Aronow J, Kaimal V, Jegga AG, Grimmond S, McMahon AP, Patterson LT, Little MH, Potter S. Atlas of gene expression in the developing kidney at microanatomic resolution. (2008) Dev Cell 15(5):781-91
  10. Georgas, KM, Rumballe, BA, Valerius, MT, Chiu, HS, Thiagarajan, RD, Lesieur, E, Aronow, BJ, Brunskill, EW, Combes, AN, Tang, D, Taylor, D, Grimmond, SM, Potter, SS, McMahon, AP, Little, MH. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment. (2009) Dev. Biol (In  press, accepted May 29 2009)