Russell Lab @ UIC

Physiology | Biophysics | Bioengineering


Research Projects

Overview
Dr. Russell's scientific experience and productivity encompass multiple disciplines and demonstrates collaboration between quantitative biology, bioengineering, physiology and chemistry. As a Professor of Physiology, Biophysics, Bioengineering and Medicine, Brenda's work is supported by NIH for two collaborative projects, one on heart failure for regulation of remodeling of cell shape, and one for the development of a novel, biomimetic cardiac regeneration therapy using bioengineering approaches. Many of her studies have been done in close collaboration with clinicians (muscular dystrophies, urinary incontinence, heart failure).

Cardiac Cell Adaptation

Mechanical Activity and Myocyte Remodeling

Collaborators: R. John Solaro PhD and E. Douglas Lewandowski PhD from UIC; Allen Samarel MD and Pieter De Tombe PhD from Loyola University Medical Center

Heart failure is one of the leading causes of death, disability and hospitalization in the western world. It occurs when the heart cannot pump effectively and is unable to meet the body's need for blood and oxygen. 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. The central hypothesis is that altered signaling at the level of sarcomeric proteins occurs in the course of compensation to hemodynamic stressors leading to hypertrophy. This altered signaling is a significant factor in the decompensation leading to pump failure. The overall objective of the Russell group is to define the pathways that regulate myocyte sarcomere remodeling, which is a crucial component of this theme. Our aims are based on data strongly supporting the role of specific protein phosphorylations in these processes and address novel questions regarding the molecular mechanisms of these modifications.

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.

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.

Cardiac Regeneration

Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds

Collaborators: Paul H. Goldspink PhD, Department of Physiology, Medical College Wisconsin and Tejal A. Desai PhD, Department of Bioengineering & Therapeutic Sciences and Department of Physiology, University of California, San Francisco

Five million heart failure patients in the US have poor cardiac pumping due to irreversible damage of the contractile myocytes. Thus, recovery of cardiac function by cell and tissue engineering is highly desirable. The novel approach proposed in this application combines bioengineering and cell biology-based techniques to directly target the regeneration of heart muscle, which is an important clinical problem not well addressed by current therapies. We have systemically delivered an artificial stabilized form of the mechano-growth factor (MGF), (24 amino acid, E-domain peptide from the prohormone) that is a member of the insulin-like growth factor (IGF) family and shown recovery of function in failing mouse hearts along with the mobilization of resident progenitor cells. We take advantage of the natural repair capacity of the heart by providing a microrod scaffold (MRS) to not only deliver the native, rapidly degradable MGF, but also provide local mechanical and topographic cues necessary for proper cellular connectivity and differentiation. Our overall hypothesis is that timed release of MGF and IGF-1 delivered locally by the MRS regenerates and strengthens the damaged myocardium without harmful side effects. This is tested on progenitor/stem cells and cardiac myocytes in culture and in animal models.

Aim 1 determines the effect of stiffness variation on cells grown in 3D microrod scaffolds. We optimize MRS characteristics for regulation of cell proliferation, lineage commitment, differentiation, contractile maturity and connectivity of stem cells and cardiac myocytes.

Aim 2 determines the effect of growth factor (GF)-loaded MRS in environmental conditions that mimic the normal and ischemic heart. We characterize encapsulation efficiency, GF biostability, and acellular release kinetics of the eluting MRS in vitro. We determine effects of GF release from MRS on proliferation and migration of progenitor/stem and neonatal rat ventricular myocytes to establish changes in gene expression and cell survival under culture conditions that mimic the normal and ischemic heart.

Aim 3 determines the cellular, molecular and functional gains that occur at different stages following myocardial infarction after MRS delivery of GFs to the border zone of an infarct. We examine how GF release affects the migration and differentiation of cardiac progenitor cells in vivo. We examine the beneficial effects of localized MGF peptide delivery on cardiac function, prevention of cardiac myocyte apoptosis, prevention of adverse cardiac remodeling, and reduced scar formation.

Our long-term goal is to develop microrod MGF therapy that supports the regeneration of cardiac muscle to regain cardiac function in the failing human heart.



Last updated November 18, 2011
© Copyright 2000-2012 Brenda Russell, PhD