The Tsui laboratory investigates the molecular mechanisms by which glomerular podocytes respond and adapt to injury. Podocytes, which are critical in the formation of glomerular filtration barrier at the blood-urine interface, are one of the predominant cell types affected by diabetic nephropathy and other non-diabetic glomerular diseases. The laboratory is also interested in the morphologic and functional changes that podocytes undergo during development, maintenance, and disease processes. Our studies utilize transgenic and conditional knockout mice coupled with molecular, immunological, and biochemical approaches.
We have demonstrated recently that the growth factor glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine, Ret, are upregulated selectively by podocytes in animal models of glomerular disease. We hypothesize that the GDNF-Ret signaling pathway constitutes a novel adaptation mechanism important for the injury response and maintenance of podocytes. We have generated podocyte-specific Ret conditional knockout mice to study the importance of this GDNF-Ret signaling pathway.
We have also recently developed a biochemical purification method combined with proteomic analyses of podocyte foot process and slit diaphragm-enriched fractions in order to identify novel proteins that are critical for podocyte differentiation and morphology. Slit diaphragms are critical elements of the final filtration barrier and disruption of these cell-cell contact and structural elements of podocyte foot processes occur early in the development of many glomerular diseases.
Link to PubMed Citations
Pierchala BA, Muñoz MR, Tsui CC. 2010. Proteomic analysis of the slit diaphragm complex: CLIC5 is a protein critical for podocyte morphology and function. Kidney Int. 2010 Jul 21.
Tsui CC, Pierchala BA. 2010. The differential axonal degradation of Ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor. J Neurosci. 2010 Apr 14;30(15):5149-58.
Tsui, C.C. and Pierchala, B.A. 2008. CD2AP and Cbl-3/Cbl-c constitute a critical checkpoint in the regulation of Ret signal transduction. J. Neurosci. 28, 8789–8800.
Pierchala, B.A.,Tsui, C.C. , Milbrandt, J. and Johnson, Jr, E.M. 2007. NGF augments the autophosphorylation of Ret via inhibition of ubiquitin-dependent degradation. J. Neurochem. 100, 1169-1176.
Tsui, C.C., Shankland, S.J., Pierchala, B.A. 2006. Glial cell line-derived neurotrophic factor and its receptor Ret is a novel ligand-receptor complex critical for survival response during podocyte injury. JASN. 17, 1543-1552.
Yu, A.L., Uttenreuther-Fischer, M.M., Huang, C., Tsui, C.C., Gillies, S.D., Reisfeld, R.A., Kung, F.H. 1998. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. Journal of Clinical Oncology. 16, 2169-80.
Tsui, C.C., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Barnes, C. and Worley, P.F. 1996. Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. Journal of Neuroscience. 16, 2463-78.
Calco, G.N., Stephens O.R., Donahue, L.M., Tsui, C.C.*, and Pierchala, B.A.* 2014. CD2AP enhances Cbl-3/c-mediated Ret ubiquitination and degradation via its amino-terminal SH3 domains. J. Biol. Chem, 289(11):7307-19.