Focal segmental glomerular sclerosis (FSGS) is a kidney lesion seen in a number of disease states, and contributes significantly to the population of patients with end-stage renal disease. Several inherited forms of FSGS have been described. Mutations identified to date involve proteins expressed in the podocyte, and studies of inherited FSGS have furthered our understanding of how podocytes help maintain the filtration barrier that prevents protein from spilling into the urine. Recently, mutations in TRPC6, a calcium channel, have been identified as causing an autosomal dominant form of FSGS. Mutations have been found to involve several different areas of the TRPC6 protein, yet how they might affect TRPC6 function is unclear. We propose several lines of investigation to characterize these mutations in cell based and in vitro systems, including possible effects on protein stability, localization, phosphorylation, and channel activity. In addition, we plan to assess the ability of these mutant channels to multimerize with other TRPC family members as well as bind to key components of the podocyte slit diaphragm. These studies will further open new lines of investigation into how TRPC6 function is crucial for proper podocyte function. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK074308-02
Application #
7304051
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Rankin, Tracy L
Project Start
2006-06-30
Project End
2008-06-29
Budget Start
2007-06-30
Budget End
2008-06-29
Support Year
2
Fiscal Year
2007
Total Cost
$53,992
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Schlöndorff, Johannes; Del Camino, Donato; Carrasquillo, Robert et al. (2009) TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol 296:C558-69
Weins, Astrid; Schlondorff, Johannes S; Nakamura, Fumihiko et al. (2007) Disease-associated mutant alpha-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc Natl Acad Sci U S A 104:16080-5
Schlondorff, J S; Mendez, G P; Rennke, H G et al. (2007) Electrolyte abnormalities and progressive renal failure in a cancer patient. Kidney Int 71:1181-4
Schlondorff, Johannes S; Pollak, Martin R (2006) TRPC6 in glomerular health and disease: what we know and what we believe. Semin Cell Dev Biol 17:667-74