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Cynthia C. TsuiNeurotrophic Factors in Kidney Development and Disease Research Assistant Professor PhD 1996 Johns Hopkins School of
Medicine |
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Cynthia C. TsuiNeurotrophic Factors in Kidney Development and Disease Research Assistant Professor PhD 1996 Johns Hopkins School of
Medicine |
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| Electron microscopic image of a rat glomerulus. The
large arrow indicates a podocyte cell body and a small
arrow indicates a foot process that extends from the ends of podocytes and interdigitates with neighboring foot processes. Small arrowhead shows a slit diaphragm which connects the interdigitating foot processes and forms the final blood-urine barrier. |
Glomerular diseases are the most common cause of chronic and end stage renal disease in the US. Podocytes, which form the final filtration barrier at the blood-urine interface, are the predominant cell type affected by diabetic nephropathy (DN) and other non-diabetic kidney diseases. Podocyte loss, either by cell death or detachment, is directly related to the progression of glomerular disease. Thus, understanding how podocytes respond to injury is critical for the development of therapeutic interventions.
Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated selectivey by podocytes in animal models of glomerular disease (see immunohistological staining below). GDNF is a potent survival factor for neurons which, along with the homologous family member neurturin, have been studied intensively because of their therapeutic promise in Parkinson's disease. We have shown that podocytes, which share many similarities to neurons, are protected by GDNF during in vitro injury models. We hypothesize that GDNF and Ret constitute a novel, protective signaling pathway enacted by podocytes as an adaptive response to injury. It is our goal that by understanding the survival-promoting pathways induced by podocytes in response to injury, novel therapies for glomerular disease will be uncovered.
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Immunohistological staining showing the upregulation
of Ret protein specifically in podocytes (arrowheads) after both non-immune and immune-mediated rodent models of human glomerular diseases. Puromycin aminonucleoside nephrosis (PAN, panels a-c), is a model of membranous nephropathy and passive Heymann nephritis (PHN, panels d-f), is a model of focal segmental glomerulosclerosis. |
To test the hypothesis that GDNF functions as an adaptive response to halt or slow the progression of glomerular disease in vivo. Both molecular genetic and immunologic methods of blocking GDNF in vivo will be applied to animal models of focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy to determine whether disease progression is exacerbated.
To test the hypothesis that the administration of exogenous GDNF or neurturin is a novel therapy in animal models of FSGS and diabetic nephropathy.
To test the hypothesis that Ret9 and Ret51 have distinct functions in podocyte development and adaptation to glomerular injury. The two Ret isoforms, Ret9 and Ret51, have unique biochemical properties that likely translate into unique functional properties. This hypothesis will be tested in podocytes in vitro and in vivo.
Ultimately, the goal of these studies is to understand the mechanisms by which glomerular cells respond and adapt to injury, with the intent that this knowledge will be applicable to the development of new therapeutic strategies for these debilitating kidney diseases.
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Co-immunofluorescent staining of Ret (green, panel a) and WT-1(red, panel b) in fixed rat kidney tissue. Ret receptor staining is localized to the cell surface and is co-expressed in the same cell with WT-1 (merge, panel c), a known nuclear podocyte-specific marker. |
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. J Am Soc Nephrol 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 (6), 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 (8), 2463-78.