Canonical transient receptor potential (TRPC) channels are linked in maladaptive cardiac hypertrophy mediated by calcineurin-nuclear factor of activated T cells (Cn- NFAT) signaling. Yet, the regulation of channel activity is not well understood. Our lab has reported on one regulatory mechanism of by which PKG phosphorylation inhibits TRPC6 activity. Studies in HEK293 cells indicate TRPC channel activity may also be modulated by gating of stromal interacting protein-1 (Stim1) which was recently reported to contribute to the hypertrophic response in vivo. Preliminary data suggests that Stim1 and TRPC6 channel coupling may influence PKG inhibition of the channel. The proposed work has the potential to advance our understanding of the molecular mechanisms of cardiac hypertrophy and subsequent heart failure. By better understanding the modulation of TRPC channels, which are important in experimental and models of cardiac pathology and are also upregulated in human heart disease, we will learn clues about targets for therapy. We hypothesize that STIM1 interacts with TRPC3 and TRPC6 channels in the cardiomyocyte leading to increased calcium entry and hypertrophic signaling mediated by NFAT. Additionally, we propose that the coupling of Stim1 and TRPC3/6 channels in the cardiomyocyte prevents PKG phosphorylation. We will test this by examining the calcium influx in isolated cardiomyocytes, and in vivo we will explore the interaction between Stim1 and TRPC channels in rodent models of cardiac hypertrophy.

Public Health Relevance

Canonical transient potential receptor (TRPC) channels play a role in the development of heart failure. It is not understood how the channel activity is regulated in the setting of cardiac pathology but stromal interaction molecule 1 (Stim1) may play an important role. We seek to explore this relationship and gain insight to development of heart failure in an effort to identify ways to inhibit the process.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL116167-03
Application #
8692593
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Meadows, Tawanna
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kooij, Viola; Venkatraman, Vidya; Tra, John et al. (2014) Sizing up models of heart failure: Proteomics from flies to humans. Proteomics Clin Appl 8:653-64