AWARD 1:   

Mechanisms and therapeutic potential of microRNA regulation by fibrillin-1

Dieter Reinhardt, PhD, Professor, Canada Research Chair in Cell-Matrix Biology, McGill University, Montreal, QC

LAY SUMMARY:

Fibrillin-1 is a protein present in the connective tissue of many organs, including blood vessels and bone. Abnormalities in the fibrillin-1 gene cause various disorders which lead to severe and continuously developing clinical complications. Examples of this include various forms of Marfan syndrome, stiff skin syndrome, dominant Weill-Marchesani syndrome, acromicric and geleophysic dysplasias, familial tall stature, ectopia lentis, among others. It is estimated that about 1 in 3,000-5,000 individuals suffer from one of these disorders, resulting in high levels of physical and mental distress for patients and families, in addition to immense costs for the health care system. Marfan syndrome is the most frequent disorder in this group.

With the financial GADA support, we have found that the molecular interaction of fibrillin-1 with connective tissue cells controls a group of very important regulatory molecules, the so-called microRNAs. These are molecules within cells that determine which proteins are produced. We have now observed, when fibrillin-1 interacts with cells, some of these microRNAs are produced more and others less. This has consequences on how the cells function. It changes for example how certain growth factors are produced and become activated. One example is the growth factor TGF-beta, which is known to play a role in the development of the clinical problems in Marfan syndrome. Another example is the effector protein ERK1/2, which is also important for disease progression. We have identified in the first period of this project three microRNAs that can influence the activity of both, TGF-beta and ERK1/2. Together, these data identify fibrillin-1 as a regulator of miRNA expression relevant to Marfan syndrome disease mechanisms, and highlight the three identified microRNAs as promising candidates to further explore their therapeutic potential in experimental disease models. The new data also facilitated recently a larger grant application to the Canadian Institutes of Health Research.
 

AWARD 2:

The Effects of a Physical Activity Intervention on Aortic Health in Children and Adolescents with Marfan syndrome (MFS)

Kevin Harris, MD, Assistant Professor and Clinician Scientist, University of British Columbia, Vancouver

LAY SUMMARY:

Marfan syndrome is an inherited disorder of connective tissue in the body (such as in the heart and muscles) affecting approximately one in 3000 people. One of the major blood vessels in the heart (called the aorta), which is important to take blood away from the heart to the rest of the body, becomes weak over time putting patients at risk of death if it breaks. Strenuous activity is discouraged in Marfan syndrome as it can cause extra stress on the aorta and may damage it. However, being inactive is also not good for the health of the aorta and physical activity may improve the elasticity of the aorta. We currently do not know if the health of the aorta can improve with physical activity in people, but a recent animal study saw more elastic aortas following exercise. Increasing physical activity is also known to improve quality of life in many patient groups. Thus, we expect that Marfan patients will have improved aortic health and quality of life after increasing their physical activity over a period of time.

The present study involves a 6-months of regular physical activity in young Marfan patients, 10-19 years of age. At the start and finish of the study, patients will have an echocardiogram (which takes pictures of heart and aorta), will provide a blood sample, and complete a Quality of Life Questionnaire. The blood sample is for measuring substances in the blood that are related to Marfan syndrome, and are higher than are found in healthy children. Also, these markers are known to decrease with exercise. Patients will be given suggestions on how they can increase their physical activity that is suited to their current needs, involves activities they like, and is safe for them to do. They will wear a Fitbit device throughout the study that will track their steps and heart rate. Patients will be able to regularly talk with researchers and other participants in the study, via emails, text messaging, and a Fitbit forum. The proposed study can improve the health and quality of life for children and teens with Marfan syndrome by using an enjoyable, inexpensive treatment that they can safely do for their entire life.

The study is met with great interest by our participants and their families, and several individuals are currently actively enrolled in the study.