Mechanical strain is a powerful stimulus for shape and size remodeling of cardiac myocytes in normal and pathological situations. Indeed, the major change in shape that precedes heart failure in humans is progression to cellular elongation in dilated cardiomyopathy. The overall objective of this project is to test the hypothesis that longitudinal mechanical strain regulates cell lengthening by differential phosphorylation of focal adhesion kinase (FAK) at the costamere leading to differential actin capping by CapZ at the Z-disc and thin filament addition.
The Specific Aims are:
Aim #1 : To determine the mechanisms of anisotropic Rho family G protein phosphorylation leading to myocyte elongation. We define the subcellular events responsible for strain-induced PKCE signaling using the PKCE-over expressing (OE) mouse, and aligned 3D cultured neonatal rat ventricular myocytes (NRVM) subjected to sudden static strain as model systems.
Aim #2 : To test the hypothesis that PKC-dependent FAK serine phosphorylation is required for the costameric mechanosensory apparatus to detect longitudinal strain. We examine the PKC dependence of FAK serine phosphorylation in response to longitudinal vs. transverse strain in 3D NRVM cultures.
Aim #3 : To determine whether elongating myocytes have altered CapZ phosphorylation. We determine whether CapZ phosphorylations in normal mice differ from ventricular myocytes that are lengthening and whether there is differential CapZ phosphorylation in response to anisotropic mechanical inputs to NRVM aligned 3D culture.
Aim #4 : To test the hypothesis that CapZ phosphorylation and PIP2 binding alter actin capping and are required for length remodeling. We measure actin-capping dynamics of green fluorescent tagged-CapZ to determine the effect of anisotropic mechanical stimuli. We determine the mechanism of cell length remodeling by regulation of CapZ binding via phosphorylation, PIP2 and other CapZ partnering proteins. In these experiments, we use validated conditions of normal myocyte lengthening and challenge these processes with specific molecular interventions to determine the mechanisms of length remodeling.

Public Health Relevance

Heart failure is a complex disorder affecting over 5 million Americans. It remains the leading discharge diagnosis of hospitalized patients over the age of 65, and has an overall 5-year mortality rate approaching 40%, even with optimal medical therapy. Clearly, investigations targeted at improving our understanding of the fundamental process of cardiac remodeling are necessary to reduce the incidence and prevalence of this syndrome, which would have significant impact on the health and longevity of the American public.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062426-15
Application #
8629550
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$460,525
Indirect Cost
$100,547
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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