The ability of cardiomyocytes to sense and respond to mechanical stimuli is fundamental in both cardiogenesis and cardiomyopathies. However, our understanding of how mechanical stimuli modulate cardiomyocyte size still remains incomplete. This proposal focuses on a novel inhibitory mechanotransduction response that has been suggested by our studies of zebrafish 1-actinin2 (actn2), a predominant sarcomeric Z-disc protein, and tcap, a component of the Z-disc-based stretch sensor complex. Depletion of actn2 during cardiogenesis results in severely reduced ventricle chamber size, which can be rescued by arrested heart beat. At the molecular level, we found tcapb, a zebrafish cardiac tcap homologue, is activated in actn2 knockdown embryos. Depletion of tcapb rescues the reduced chamber size in actn2 knockdown embryos, suggesting that transcriptional activation of tcap confers an inhibitory mechanotransduction response. In addition to heart development, activated tcap expression was detected in an adult zebrafish model of cardiomyopathy, and overexpression of tcap attenuates the enlarged heart and increases the survival rate in adult fish models of cardiomyopathy. Together, our preliminary observations support the central hypothesis of this proposal predicting that transcriptional activation of Tcap confers inhibitory mechanotransduction response incurred by mechanical stimuli that reduces ventricular chamber size. We will test this hypothesis by the following three specific aims.
In Specific Aim 1, we propose to validate the hypothesis that the reduced ventricular chamber size in actn2 knockdown is ascribed to mechanical stimuli that inhibit ventricular chamber enlargement.
In Specific Aim 2, we propose to validate the hypothesis that transcriptional activation of Tcap confers the inhibitory mechanotransduction signaling to control ventricular chamber size.
In Specific Aim 3, we propose to test the hypothesis that transcriptional activation of Tcap occurs in various adult cardiomyopathies and can be enhanced for cardioprotective benefits. The information gained from here will provide novel insights into the pathophysiology of Tcap-based cardiomyopathy and muscular dystrophy type 2G. Moreover, because the mechano-signaling in cardiomyocytes plays a pivotal role in the pathogenesis of both acquired and inheritable cardiomyopathies, our proposed research will have broad impacts on cardiomyopathies of different etiologies.

Public Health Relevance

This proposal studies how mechanical stimuli regulate the ventricle size, a fundamental question during both cardiogenesis and adult cardiomyopathy. We focus our efforts on an inhibitory mechanotransductive response that can be enhanced to achieve therapeutic benefits for cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081753-08
Application #
8520377
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2005-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$375,326
Indirect Cost
$137,326
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Fei, Peng; Lee, Juhyun; Packard, René R Sevag et al. (2016) Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function. Sci Rep 6:22489
Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2016) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 1:
Shih, Yu-Huan; Zhang, Yuji; Ding, Yonghe et al. (2015) Cardiac transcriptome and dilated cardiomyopathy genes in zebrafish. Circ Cardiovasc Genet 8:261-9
Yang, Jingchun; Hartjes, Katherine A; Nelson, Timothy J et al. (2014) Cessation of contraction induces cardiomyocyte remodeling during zebrafish cardiogenesis. Am J Physiol Heart Circ Physiol 306:H382-95
Li, Xiaoping; Luo, Rong; Gu, Haiyong et al. (2014) Cardiac troponin T (TNNT2) mutations in chinese dilated cardiomyopathy patients. Biomed Res Int 2014:907360
Yang, Jingchun; Shih, Yu-Huan; Xu, Xiaolei (2014) Understanding cardiac sarcomere assembly with zebrafish genetics. Anat Rec (Hoboken) 297:1681-93
Ding, Yonghe; Liu, Weibin; Deng, Yun et al. (2013) Trapping cardiac recessive mutants via expression-based insertional mutagenesis screening. Circ Res 112:606-17
Campbell, Jarryd M; Hartjes, Katherine A; Nelson, Timothy J et al. (2013) New and TALENted genome engineering toolbox. Circ Res 113:571-87
Yang, Jingchun; Xu, Xiaolei (2012) α-Actinin2 is required for the lateral alignment of Z discs and ventricular chamber enlargement during zebrafish cardiogenesis. FASEB J 26:4230-42
Yang, Jingchun; Xu, Xiaolei (2012) Immunostaining of dissected zebrafish embryonic heart. J Vis Exp :e3510

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