# Understanding the mechanisms of TRPC6 mediated FSGS

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $393,750

## Abstract

PROJECT SUMMARY
Focal segmental glomerulosclerosis (FSGS) is a significant cause of chronic kidney disease, has few effective
treatment options, and usually progresses to end-stage renal disease (ESRD). FSGS has a substantive
genetic component. Study of gene mutations that cause FSGS has provided invaluable insight into normal
glomerular function and the disease pathogenesis of FSGS.
Mutations in TRPC6 are a known cause of FSGS. In addition, TRPC6 levels are often increased in more
common forms of kidney disease, implying that TRPC6 activity may impact both acquired and genetic forms of
FSGS. TRPC6 is an ion channel found on the surface of cells, making it an attractive pharmacologic target.
However, two key questions about TRPC6 and the development of FSGS remain unanswered. Is it simply that
excess TRPC6 activity is detrimental to glomerular function, or is TRPC6 like Goldilocks, with either too much
or too little detrimental? Which of the multiple signaling pathways intersecting with TRPC6 are relevant to the
development of glomerular pathology? We have created novel animal models - mice with the equivalent of a
human FSGS mutation in Trpc6 and others with a dominant negative (DN) Trpc6 mutation - to be able to
address these questions. Our experimental plan has three Specific Aims with the goal of providing answers to
the above questions: (1) To ascertain whether mice with FSGS- or DN-mutations in Trpc6 develop FSGS with
age or require a “second hit” to manifest disease. (2) To characterize the effect of TRPC6 mutations on
podocyte behaviors known to be affected in FSGS, focusing on regulation of their actin cytoskeleton,
calcineurin-NFAT signaling, and cell death. (3) To determine the genes necessary for mutant TRPC6-induced
cell death.
Our proposed studies have the potential to significantly enhance our understanding of FSGS. They will help us
understand how increased and decreased TRPC6 activity alters glomerular response to stress, and will clarify
which of the known signaling pathways activated by TRPC6 mediate pathology. The research has the
potential to uncover novel molecular mechanisms involved in regulating TRPC6 and promoting FSGS.
Ultimately, the results will help determine whether blocking TRPC6 activity might be a potential, and much
needed, new therapeutic approach for the treatment of FSGS.

## Key facts

- **NIH application ID:** 9830064
- **Project number:** 5R01DK115438-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JOHANNES S SCHLONDORFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2017-12-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830064

## Citation

> US National Institutes of Health, RePORTER application 9830064, Understanding the mechanisms of TRPC6 mediated FSGS (5R01DK115438-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830064. Licensed CC0.

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