Using Zebrafish Models to Study Cardiovascular Disease

Maryline-squareprofile.jpgMaryline Abrial, PhD, is a postdoctoral research fellow in the Burns Lab at the Cardiovascular Research Center at Massachusetts General Hospital. She took part in a science communication internship at the Mass General Research Institute this fall. She wrote this first-person account of her life as a researcher as part of her internship.

Background and Education

I think what drew me to the biological sciences was a passionate high school biology teacher, who was great mentor and advisor over the years of my undergraduate and graduate training.

I have always found biological processes fascinating. The complexity of them can be very challenging, but understanding and deciphering even a small part feels very rewarding when you can impact human diseases.

Since I started my graduate studies in France in University Claude Bernard in Lyon, I have focused on cardiovascular science. During my PhD, I studied myocardial infarction, which is more commonly known as a heart attack.

My work focused on understanding cellular interactions and especially how non-contractile cell types can help to protect the cells in charge of contraction after an injury such as a heart attack.

After my PhD, I decided to pursue my work in the field of cardiovascular sciences in the exciting scientific environment that Boston offers. I joined the laboratory of Dr. Caroline Burns and Dr. Geoffrey Burns in the Cardiovascular Research Center at Massachusetts General Hospital.

The zebrafish as a model organism

The Burns laboratory studies heart development and regeneration in a particular animal model—the zebrafish.

Unlike humans, zebrafish can regenerate new cardiac tissue after an injury such as a heart attack, which makes them a great model to study the cellular and molecular mechanisms involved in cardiac regeneration.

The zebrafish is also a powerful vertebrate model to study cardiovascular developmental biology because of its rapid external development, the large number of eggs that can be obtained and, more importantly, its beating developing heart that can be observed only 24 hours after fertilization of the egg.

While the zebrafish heart, which is comprised of a single ventricle and atria, is a simpler version of the human heart, the mechanisms regulating its development share much in common.

Investigating aortic arch development

After joining the Burns lab, I slowly became familiarized with zebrafish, and all the genetic tools and imaging techniques that make them such an attractive research model.

I worked closely with a senior research fellow who was studying the development of the great arteries of the heart (also named Pharyngeal Arch Arteries, or PAAs) during embryonic development.

In humans, the PAAs start off symetrically, but then undergo intensive remodeling before taking their final asymetrical shape. Impaired remodeling of those PAAs during development can lead to congenital heart diseases such as Tetralogy of Fallot.

This remodeling process is similar throughout vertebrates, and the zebrafish is a great model organism to visualize and study the cellular progenitors that give rise to these specific arteries.

Using the zebrafish to perform small molecule screening, we uncovered a specific signaling pathway that is involved in the differentiation of great arteries’ cellular progenitors. Using genome-editing technologies, we engineered zebrafish lacking the function of two genes that are involved in this pathway.

Surprisingly, we found that those zebrafish embryos presented a phenotype similar to a human disease called Marfan Syndrome (MFS), a genetic disorder that affects the connective tissue.

People affected by MFS present symptoms in different parts of their bodies, but the most severe ones are linked to the cardiovascular system and include widening or aneurysm of the basis of the aorta (aortic root), which is the main artery carrying blood away from the heart.

This aneurysm can cause a dissection or a tear in the vessel, which will weaken it over time and could lead to a life threatening rupture.

We found that our zebrafish models, when engineered to lack the expression of these two genes, rapidly exhibit an impressive aortic aneurysm (in only 5 days) in a location that is anatomically equivalent to where human aortas are susceptible to developing aneurysm in MFS.

We have analyzed these zebrafish aneurysms and found several molecular hallmarks of the human disease, suggesting that the mechanisms by which zebrafish embryos develop aortic aneurysms are similar to those in Marfan patients.

The Marfan Foundation has funded my research for two years beginning in July of 2016. We are using zebrafish models in combination with genetic tools and microscopic imaging to complement ongoing work in the aneurysm field.

Although tremendous progress has been made in the past decade in the aneurysm research, several questions remain unknown regarding the drivers of the disease.

Current preventive medical therapies for Marfan patients are mainly aimed to reduce blood pressure to decrease the risk of life-threatening complications or to undergo cardiac surgery to repair the aortic root. But so far no therapy has been discovered that prevents or reverses the process of aortic dilation itself.

Because zebrafish embryos are so small and readily available, we can screen large collections of small molecules to looks for candidates that will prevent or cure aortic aneurysm in zebrafish.

In the long run, we hope that any small molecule that suppresses zebrafish aneurysm could be therefore tested in other laboratory models and eventually in humans to learn if they will prevent and/or reverse Marfan Syndrome-associated aneurysm.

The zebrafish gives us a tremendous advantage in studying the pathophysiology of cardiovascular diseases. With the progress of genome editing technologies now readily available, this model can be used to study specific cardiovascular diseases and help to further validate and understand the function of candidate genes identified in human cohorts affected by cardiovascular diseases.

Thank You Postdocs!

As National Postdoc Appreciation Week comes to a close, we want to thank postdocs across the country, and especially those at Mass General, for all their hard work and dedication to research and scientific discovery.

Here at Mass General, we have over 1800 postdoctoral fellows who collectively contribute to over 6100 active research projects.

Earlier this week we celebrated our postdoc cohort with an ice cream social and asked them what they love most about research. Here’s what a few of them had to say…

IMG_1362

IMG_1358

IMG_1355.JPG

IMG_1356.JPG

IMG_1357

IMG_1360.JPG

IMG_1361

IMG_1359.JPG

Meet a Mass General Postdoc: Amy Tsurumi

In honor of National Postdoc Appreciation Week, all this week we’ll be sharing profiles of just a few of our amazing Mass General postdocs to highlight their research and what inspires them.

Postdoc week Tsurumi.png

Our fourth and final featured postdoc this year is Amy Tsurumi, PhD, a research fellow in the Rahme Lab.

Where did you get your PhD from?

University of Rochester School of Medicine and Dentistry

What questions are you asking in your current research? What do you hope to find out?

My research is elucidating epigenetic mechanisms of host susceptibility and response to infections using Drosophila, mice and tissue culture Pseudomonas aeruginosa infection models.  I hope to identify specific histone post-translational modification marks and genomic loci that are relevant and explore the possibility of alleviating the negative impact of pathogenic encounters by reversing these epigenetic marks.  Given the rise of antibiotic resistant bacteria, developing host-targeted methods as an alternative approach may be significant.  I also conduct epidemiological and biomarker studies for prediction of vulnerability to infections and infections-related outcomes in burn and trauma patient cohorts. 

What drew you to this field?

My father was a physician-scientist with a microbiology research background and fascination in human genetics, so I grew up being curious about the field of biomedical sciences.  As a graduate student, I learned about epigenetics for the first time and studied histone lysine demethylases, a relatively novel class of epigenetic regulators back then, which I found to be absolutely exciting.  I was thrilled to join the Rahme lab where I was lucky to have been given the opportunity to continue to conduct epigenetics research that I am interested in, but shift from the context of Drosophila development to host-microbe interactions using a variety of model organisms and also incorporate patient cohort clinical research.

What is a typical day like for you?

It is difficult to define a “typical” day, which I actually enjoy. Most days, I spend the majority of the time running experiments on the bench or conducting patient data analyses.  When there are grant/fellowship deadlines, I spend the day focusing on writing.  I find myself to be extremely lucky that there are many different types of experimental methods I get to do and various model organisms available in the Rahme lab.  The variety of techniques offered has given me an incredible learning experience thus far.

What do you like most about being a postdoc at MGH?

I am awed by the highly collaborative environment at MGH.  The Rahme lab is diverse in terms of scientific background (and home countries!) and I am very thankful to my mentor for the excellent mentorship and also to other postdocs around me, especially labmates and floormates for the invaluable input and help I receive daily.  I also feel fortunate to be part of collaborative projects with various PIs within MGH and around the globe, as well as the vast amount of resources offered by neighboring labs, MGH core facilities and other Harvard campuses.  All the research that goes on every day at MGH is stimulating and my mentor and colleagues I have the opportunity to work with are inspiring.

Meet a Mass General Postdoc: Xavier Fernando Vela Parada

In honor of National Postdoc Appreciation Week, all this week we’ll be sharing profiles of just a few of our amazing Mass General postdocs to highlight their research and what inspires them.

Postdoc week Vela Parada.png

Xavier Fernando Vela Parada is a research fellow in the Thadhani Lab in the Nephrology Division.

Where did you get your MD from?

I studied medicine in my home country El Salvador, Central America.

What questions are you asking in your current research? What do you hope to find out?

At the Thadhani lab we focus on finding new ways to detect and treat various forms of kidney disease. We hope that we will be able to find new markers and new therapeutic agents that will allow us to treat and detect kidney disease in its early stages as well as its complications.

What drew you to this field?

Nephrology is the basis of medicine. Since I was in med school I was impressed at the way the kidneys tightly regulate the human physiology; this was my favorite subject while studying to become a physician. Chronic kidney disease is problem of enormous proportions and I feel committed to work towards finding a solution for our patients.

What is a typical day like for you?

A typical day will include discussion with my PIs about new research questions and future directions for our research. Also, when working with patients I make sure they understand how much we value them and how important their contribution is to science. I also work closely with other staff, making sure our study samples are collected and stored properly. Normally I will also reach out to younger staff to share my passion for kidney research.

What do you like most about being a postdoc at MGH?

I love the fact that being at MGH gives me the exposure to a vast array of fantastic clinicians, scientists, service and administrative personnel. Each one of them contribute in one way or another in order to achieve our end goal which is to improve patient care. At the same time MGH made me feel welcome from the very first day; in a place so diverse like this I encountered a new family.

Meet a Mass General Postdoc: Echoe Bouta

In honor of National Postdoc Appreciation Week, all this week we’ll be sharing profiles of just a few of our amazing Mass General postdocs to highlight their research and what inspires them.

Meet Echoe Bouta, PhD, a research fellow in the Department of Radiation Oncology.

Postdoc week Bouta (1)

Where did you get your PhD from?

University of Rochester

What questions are you asking in your current research? What do you hope to find out?

Lipedema is a chronic disorder that results in increased fat in the lower limbs and manifests as dramatic, painful swelling. Clinical studies demonstrate that patients present with at least partial lymphatic dysfunction, which worsens until lymphedema occurs. As the etiology is largely unknown, treatments are often ineffective, demonstrating the need to understand the relationship between fat and lymphatic capability.  The questions I hope to answer are:

      •  How does increased adiposity impair lymphatic function in an animal model of obesity?
      • Can we target key pathways in this process to improve lymphatic function?

The answer to this questions will hopefully catalyze new treatments for lipedema.

What drew you to this field?

The lymphatic research field is relatively young compared to other research fields.  I believe that we have only started to discover the importance of the lymphatic system in multiple disease states and it is exciting to be part of that.

What is a typical day like for you?

Much of my project involves imaging of the lymphatic system under different contexts, such as obesity or after delivery of a drug. Therefore, a typical day for me is a mix of in vivo experiments, data analysis and writing.

What do you like most about being a postdoc at MGH?

The people.  We are surrounded by talented scientists from a variety of fields that results in a very interdisciplinary research environment.

Meet a Mass General Postdoc: Robert Lochhead

This week is National Postdoc Appreciation Week, a time to recognize the significant contributions that postdoctoral scholars make to the research community.

In celebration, all this week we’ll be sharing profiles of just a few of the amazing postdocs here at Mass General to highlight their research and what inspires them.

First, we’d like to introduce Robert Lochhead, a clinical research fellow for the Center for Immunology and Inflammatory Diseases in the Division of Rheumatology, Allergy & Immunology:

Postdoc week Lochhead.png

Where did you get your PhD from?

I got my PhD in microbiology and immunology from the University of Utah School of Medicine.

What questions are you asking in your current research?

I am studying the immunopathology of Lyme arthritis, and the relationship between infection and autoimmunity.

What do you hope to find out?

From a microbial and immunological perspective, Lyme disease is a fascinating human infectious disease model. The pathogen, Borrelia burgdorferi, is highly adapted to hiding from the immune system within connective tissue, resulting in infections that can go undetected for many months. What’s more, there is a wide range of disease manifestations and severity, depending on both host and pathogen factors. Lyme arthritis, the most common late-disease manifestation, may persist or worsen even after the bacteria have been cleared by antibiotic therapy, called post-infectious Lyme arthritis. My research is focusing on how B. burgdorferi infection and subsequent tissue damage may trigger chronic autoimmune arthritis, with the hope of determining mechanisms of how infection may induce autoimmunity.

What drew you to this field?

As a young graduate student interested in host-pathogen interactions, I was attracted to the immunology of Lyme arthritis as a model of studying infection-induced autoimmunity. I’ve stuck with Lyme disease ever since, first in mouse models as a graduate student, now in humans as a postdoc.

What is a typical day like for you?

I spend most of my time analyzing big RNA sequencing datasets, in the microscope room, collecting and processing clinical samples, and writing grant applications and manuscripts. Right now my typical day is mostly writing.

What do you like most about being a postdoc at MGH?

Without a doubt, the best thing about being a postdoc here at MGH is the opportunity to collaborate with wonderful clinicians and patients who are so invested in the research side of human disease. Seeing the impact of these diseases on patients brings an urgency and focus to my research that will certainly shape the rest of my scientific career.