Our basic and translational research is focused on the mechanisms by which the heart maintains cardiac function and recovers after injury. Based upon this work we have helped to develop new ideas for treating heart failure.
Neuregulin and the Cardiovascular System
Neuregulin, a subset of the endothelial growth factor family of proteins known to play a role in vertebrate cardiac embryogensis, is re-activated in the adult heart during injury and changes in hemodynamic load. While in healthy subjects the level of neuregulin correlates with cardiopulmonary fitness, neuregulin levels correlate to cardiac stress in heart failure patients.
Neuregulin /ERBB Receptor Signaling
In response to stress, cardiac microvascular endothelial cells activate ERBB receptors in neighboring cells by proteolytically releasing NRG-1β. Depending on the cell type and context of release, NRG-1β activates one or more signaling cascades, including mitogen-activated protein kinase (MAPK), PI3K/AKT, p70/S6K, and Src/FAK pathways.
Microenvironmental Regulation of Cardiac Regeneration
Intramyocardial microenvironment determines the fate of human resident cardiac progenitor cells. We have recently identified a population of human progenitor cells that are characterized by the expression of both the CD105 cell marker and GATA-4 transcription factor.
Microenvironmental factors which induce activation of Wnt signaling results in generation and expansion of cardiac progenitors (Aisagbonhi et al, 2011).
Neuregulin-1β induces embryonic stem cell cardiomyogenesis via ErbB3/ErbB2 receptors (Hao et al, 2014). Cardiac stem/progenitor cells express ERBB2 and ERBB3 receptors and their stimulation with neuregulin-1 prevents differentiation towards myofibroblasts, reducing cardiac remodeling after heart injury (Galindo et al., 2014).
Our study identified A2B adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the heart. (Ryzhov et al, 2012).
Microenvironmental factors which mediate activation of Wnt-, ERBB- and AR- dependent signaling pathways promote generation, expansion and cardiomyogenic differentiation of resident CD105+CD31-CD45- cardiac progenitors, thus contributing to the rejuvenation of heart tissue in patients with heart failure.
Other ongoing areas of investigation:
- The role of retinoids in regulation of cardiac injury and failure
- Regulation of monocyte and fibroblast biology by neuregulin/ErbB signaling.
Interactions Between Immune and Cardiac Cells During Heart Recovery After Ischemic Heart Injury
Myocardial infarction (MI) is characterized by a marked cellular inflammatory response. CD45pos immune cells rapidly infiltrate injured myocardium, their numbers peaking at day 5 after MI when they become almost as abundant as all CD45neg non-myocyte cells (endothelial cell, fibroblasts, myofibroblasts, smooth muscle cells etc) combined (Fig. 1).
Myeloid cells are the majority of infiltrating cells during acute inflammatory and early reparative phases, and contribute to both pro-inflammatory and anti-inflammatory reactions. Our laboratory is primarily interested in studying the role of myeloid cells in the activation of cardiac progenitor cells and microvascular endothelial cells. We are currently characterizing the role of immune cells in the development of specific phenotype of cardiac mesenchymal stem-like cells using in vitro co-culture of conditionally immortalized cardiac Sca-1posCD31neg cells and different subpopulations of myeloid cells, including Ly6Gpos neutrophils, Ly6Chigh and Ly6Clow/neg monocytes, F4/80pos macrophages and monocyte-derived dendritic cells, generated from bone marrow derived lineage negative hematopoietic progenitor cells (HPC). We also investigating the molecular mechanisms involved in effects of adenosine differentiated dendritic cells (ADDC) on proliferation and morphogenic activity of microvascular endothelial cells.
NRG-1/ERBB Signaling in Myeloid Cells
Neuregulins (NRGs) belong to the epidermal growth factor (EGF) superfamily of transmembrane growth factors and included four members: NRG-1, NRG-2, NRG-3, and NRG-4. Among all neuregulins, NRG-1 has been intensively studied due to its essential role in cardiac development and in regulation of the adult cardiovascular system adaptation to physiological and pathological stress. NRGs signal through neuregulin receptors which include ERBB2, ERBB3 and ERBB4. NRG-1 binds to ERBB3 or ERBB4, and induces homo- and- heterodimer formation with each other (ERBB3/4 heterodimer, ERBB4/4 homodimer) or with ERBB2 (ERBB3/2 or ERBB4/2 heterodimers). ERBB2 has no ligand binding ability; its involvement in NRG-1 signaling is dependent upon heterodimerization with ERBB3 or ERBB4. Dimerization followed by tyrosine phosphorylation results in subsequent activation of downstream intracellular mediators of signaling including PI3K/AKT, Src/FAK, extracellular-regulated kinase (ERK1/2), nitric oxide synthase and cardiac myosin light chain kinase (cMLCK) (Fig. 2).
The protective effect of NRG-1 has been shown in a variety of pathophysiological cardiovascular conditions, including ischemic and anthracycline heart injury, and heart failure. The current paradigm holds non-immune cells as a primary target for protective effects of NRG-1. Our preliminary data, however, indicate that human monocytes express ERBB2 and ERBB3 receptors and NRG-1 signaling pathway in myeloid cells contributes to resolution of inflammation by promoting the functional shift from cytokine-secreting “pro-inflammatory” toward phagocytic “pro-resolution” phenotype (Fig. 3).
To study this phenomenon, we have developed a novel mouse model with cell type-specific deletion of Erbb3 gene expression in myeloid cells (ERBB3MyeKO).
The Science Sketch video below describes a collaborative project with the Neurocritical Care Department to determine if high Neuregulin levels correlate with improved survival after cardiac arrest.
Mary Ann Asson Batres, PhD
Research Background & Interests: My area of professional interest is research and development of cardiovascular disease (CVD) models. Laboratory animal models of CVD are the basis for the subsequent study of pathogenesis, as well as the effectiveness of new therapeutic agents for CVD treatment. I have a background and interest on novel gene therapy technology, using modified mRNA as a trigger for signaling networks, and its application in changing the gene expression profile at different types of cardiovascular pathologies.
Outside of work: All is a very simple. Usually, as most of others, I divide my life between a work, home duties and issues for pleasure and health (exactly in this order). My best free time in home is reading fiction, I also like outside activities as hiking, jogging, travels by car, and taking care of my pets and plants. I tend to not use social media as much as I think it’s a waste of time (sorry!)
Vadim Chepurko, MSc, PhD
Research Assistant III
Research Background & Interests: I received my MSc degree in Physics and Math from Saint Petersburg State University, Russia. With additional training in molecular and radiation biophysics, veterinary technology, and biochemical engineering at The Petersburg Nuclear Physics Institute and The Veterinary Institute of Poultry Technology, Saint Petersburg, Russia. I then went on to graduate with a PhD in Biological Sciences from All-Russian Research Institute of Agricultural Radiology and Agroecology. Primary research interests include but are not limited to: animal model development and computational tools for imaging analysis, ECHO examination of mice hearts in normal and pathological conditions, and TAC surgical model of heart hypertrophy
Outside of work: I do various sports and activities. I enjoy studying my own ability related to the cardiovascular system to develop energy capacity for homeostasis support under stress load.
Joanne Taylor deKay, MS
Research Associate III
Research Background & Interests:
Cell signaling and inflammation after resuscitation from cardiac arrest
Immune response after injury or infection
Immune cell subtypes
Chemokine dynamics and profiling in cardiovascular health and disease
Neuregulin/ERBB receptor signaling
Outside of work:
Singing, cross-country skiing and snow shoeing, trail riding, swimming, sculling, hiking, cooking, reading, anything involving music.
Amanda J. (Favreau) Lessard, PhD
Research Background & Interests: I have had a diverse research background through my years of training, but though the research topic has changed through the years, my work has all heavily stemmed around Cell and Molecular Biology. My career started with my post-baccalaureate training in the Genomics Unit at Rocky Mountain Laboratories in Hamilton, Montana, a satellite campus for the National Institute of Allergy and Infectious Diseases/National Institutes of Health. I moved back to my home state of Maine as a research technologist at MMCRI before joining the University of Maine Graduate School of Biomedical Science and Engineering. My Ph.D. thesis titled “Cytokine and Epigenetic Regulation of MicroRNA in Acute Myeloid Leukemia” was completed within Dr. Pradeep Sathyanarayana’s laboratory at MMCRI. Upon searching for a postdoctoral fellowship, I knew I wanted to expand my research interests and joined Dr. Sawyer’s laboratory with a strong interest in the field of Cardio-Oncology. I aimed to bridge my knowledge of the Cancer Biology field with another area of interest, Cardiology. My research during this postdoctoral training has included studies in the effects of doxorubicin cardiotoxicity as a model of injury to investigate cell based therapies as well as understanding the role of retinoic acid in cardiac stress conditions and injury models. As my postdoctoral training had neared completion, I have begun training through the NNE-CTR at MMCRI for the Research Navigation Certificate and aim to transition into a Research Navigator role to provide my diverse background in supporting clinicians with their clinical and translational research.
Outside of work: Born and raised in Maine, I love to spend my time outdoors with my family. We enjoy various outdoor activities such as skiing, camping, kayaking, hiking, fishing and hunting. We live in too beautiful of a state to not enjoy all that Maine has to offer!
Carolyn Lucy, BS
Research Assistant III
Research Background & Interests: I graduated from University of New England in 2019 with a B.S. in Biochemistry and minor in Applied Mathematics. After graduation, I spent a summer interning at the University of Belgrade in Belgrade, Serbia, for an ongoing study on the use of polymer films for sustainable food packaging. I then worked in industry for a year before joining the Sawyer-Ryzhov team! Currently, I have been genotyping mice through PCR analysis as well as running some ELISAs for the HASH study. Additionally, I am the lab safety officer and in charge ordering supplies for the lab.
Outside of work: When not in the lab, I enjoy getting outside in numerous ways such as hiking, cross-country skiing, and kayaking. I also love to travel and visit new countries – my favorite place I’ve been so far is Istanbul and I hope to go back someday.
Research Background & Interests:
University of Michigan, USA, BA (Anthropology)
University of Michigan, USA, Graduate Studies (Anthropology and Public Health)
Outside of work: Fishing, boating, travel, music
Sergey Tsibulnikov, PhD
Research Background & Interests: I graduated from the Siberian State Medical University with a degree in biophysics, where I also received my PhD, as well as a license as a radiologist. Before joining the Sawyer/Ryzhov team, I worked for 10 years in the laboratory of experimental Cardiology, the Research Institute of Cardiology. There I mostly performed small animal surgery. Now as a postdoc I am working with isolated cardiomyocytes and learning new techniques.
Outside of work: I like to go to the gym, play basketball, ride bikes, travel, and in general any activity in nature with my family.
Jon Rud, MMC Resident- Research Rotation
Tristan Fong (Tufts University School of Medicine Maine Track Program )
Ryan Hibbs (University of Southern Maine)
Mohammed Mahdi (University of Southern Maine)
Myocardial Biology & Heart Failure Research Lab Alumni
Rutwik “Ricky” Rath
Sergey Ryzhov, MD, PhD (left) and Joanne Taylor deKay, MS (right) taking a break in the Myocardial Biology & Heart Failure Research Lab.
Joanne Taylor deKay, MS, suited up in full PPE (Personal Protective Equipment).
Two graphics above were developed from supporters of the American Heart Association’s 2020 Southern Maine Heart Walk virtual event.
Sergey Ryzhov, MD, PhD, Co-Director of the Myocardial Biology & Heart Failure Research Lab
Amanda Lessard, PhD, Research Fellow
Rutwik “Ricky” Rath, former lab member
Nancy Saldana, Community Member
Sergey Tsibulnikov, PhD, Research Fellow
2019 Lab Members
2017 Lab Members
2015-2016 Lab Members
Carolyn Lucy in Istanbul
American Heart Association Heart Walk
Sergey and Emmanuel at the Experimental Biology 2019 conference
Doug Sawyer sailing
Sarah Peterson at MMCRI Open House
Amanda Lessard and Angela Kosta take a lab break
2018 American Heart Association Heart Walk
2014 Lab Photo
MMCRI Boat Cruise