Mechanical Activity and Myocyte Remodeling

$397,375P01FY2010HLNIH

University Of Illinois At Chicago, Chicago IL

Investigators

Linked publications & trials

Paper 38050701 Paper 37737016 Paper 37603101 Paper 37551968 Paper 37398289 Paper 37122209 Paper 37115473 Paper 37102986 Paper 36695814 Paper 35654310 Paper 35444559 Paper 35316461 Paper 35236770 Paper 35020065 Paper 34820713 Paper 34734211 Paper 34707114 Paper 34541579 Paper 34018852 Paper 33781820 Paper 33740037 Paper 33723566 Paper 33666746 Paper 33595762 Paper 33594499 Paper 33590296 Paper 33389497 Paper 33334123 Paper 33298734 Paper 33135063 Paper 32742278 Paper 32210830 Paper 31998850 Paper 31684756 Paper 31353833 Paper 31312763 Paper 30955102 Paper 30808692 Paper 30578329 Paper 30567734 Paper 30529103 Paper 30523116 Paper 30499711 Paper 30370501 Paper 30019430 Paper 29884423 Paper 29704484 Paper 29631164 Paper 29625277 Paper 29598867 Paper 29352041 Paper 29275006 Paper 29034471 Paper 28782937 Paper 28780592 Paper 28735292 Paper 28648628 Paper 28379313 Paper 28130336 Paper 28104714 Paper 28066265 Paper 27911784 Paper 27557662 Paper 27486838 Paper 27233762 Paper 27199119 Paper 27190055 Paper 27185186 Paper 26944554 Paper 26858417 Paper 26847743 Paper 26779498 Paper 26702095 Paper 26678623 Paper 26553696 Paper 26549358 Paper 26488649 Paper 26464331 Paper 26453301 Paper 26432840 Paper 26429793 Paper 26386113 Paper 26157138 Paper 26065842 Paper 26045475 Paper 25952935 Paper 25740839 Paper 25688213 Paper 25593317 Paper 25463273 Paper 25424393 Paper 25416031 Paper 25296321 Paper 25280528 Paper 25273278 Paper 25260618 Paper 25260617 Paper 25252176 Paper 25217043 Paper 25183792

Abstract

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.

View original record on NIH RePORTER →