Podocyte cytoskeletal injury is characterized by dysregulation of Ca2+ signaling and increased podocyte motility, which correlate with podocyte foot process (FP) collapse and the emergence of albuminuria. Our laboratory showed that increased podocyte motility is mediated by TRPC5, an ion channel our laboratory introduced a few years ago as an important Ca2+ influx pathway in podocytes. Based on our recent work, TRPC5 channels play an important role in the emergence of albuminuria in acute models of disease. However, little is known about the role of podocyte TRPC5 signaling in the chronicity of acquired glomerular disease such as FSGS, which is the focus of this proposal. Understanding the mechanistic steps involving TRPC5 activity and how to block it is important for the many children and adults with de novo idiopathic Nephrotic Syndrome (such as FSGS), for the devastating cases of recurrence of FSGS post-transplantation and for the millions of patients with albuminuria and FSGS in the setting of diabetes and hypertension. Unfortunately, we presently lack effective treatment for these patients, so there is tremendous unmet need in this therapeutic area. Here we propose a series of detailed in vivo studies to test the hypothesis that blocking TRPC5 channels using a small molecule inhibitor can prevent progression to FSGS and kidney failure.

Public Health Relevance

The goal of this revised application is to define in vivo the molecular mechanisms by which TRPC5 channels cause proteinuric kidney disease progression, and how blocking TRPC5 channel activity may be a new therapeutic option for FSGS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099465-01A1
Application #
8760609
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2014-09-20
Project End
2019-07-31
Budget Start
2014-09-20
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$365,200
Indirect Cost
$147,700
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115