2018 Research Grants
In the proposed studies, we will use the Fbn1 mouse as a model, to better understand how defects in the fibrillin 1 protein lead to the ocular symptoms of MFS. Specifically, we will measure the strength of the zonular fibers and do a detailed microscopic analysis of the fibers. This will help us better understand why the fibers ultimately break in MFS, leading to ectopia lentis. We will also test whether tension in the zonular fibers directly influences lens growth and, if so, identify the proteins that convert zonular tension into a growth signal. Finally, we will test whether zonule proteins are synthesized throughout life. Together, these experiments will provide insights into the causes (and potential treatment) of ophthalmic disease in MFS patients.
vEDS mouse models established on two genetically-different types of mice which show a very different severity of disease. One mouse strain has a mild disease with an almost normal lifespan, while the other mouse strain shows early death from blood vessel rupture. Using advanced genetic approaches, we should be able to find specific regions of particular chromosomes that associate with this protective effect. We plan to exploit these natural differences to search for new genes that can improve the lifespan for patients with vEDS. The ultimate goal, upon learning how these newly identified genes offer protection, would be to test drugs that can mimic this effect – initially in mice but hopefully later in people with vEDS.
The purpose of this research is to develop and test a magnetic resonance imaging (MRI) strategy that has the ability to discern the make-up of the wall of the aorta. We will particularly look for a mucous-like material (glycosaminoglycan (GAG)-rich proteoglycans) that accumulates in the wall of the aorta in individuals with Marfan syndrome. This abnormal material renders the aorta susceptible to tearing. We will first undertake MRI in aortic fragments that have been retrieved from patients undergoing aortic replacement. We will then undertake MRI of individuals asked to lie in the MRI machine, and use a specialized technique that will take images of this abnormal material in their aortic wall.
These studies have the potential to open an entirely new window into evaluating the aorta in individuals with Marfan syndrome and related disorders. The approach could offer an important new strategy for customizing and personalizing their care to reduce the chances of serious aortic tearing.
2018 Victor McKusick Fellowships
It has been reported that sleep apnea is more common in people with Marfan syndrome and that it may accelerate aortic disease progression. The mechanisms proposed to explain this link can be broadly divided into two. Firstly, intermittent increases in blood pressure and heart rate that occurs with sleep apnea generate pulsatile strain on the heart and an already weak aortic wall. Another related but different mechanistic pathway is via snoring. These mechanisms may play a significant role in persons with vulnerable aortas such as in Marfan syndrome. In this project, in order to quantify the cardiovascular stress, we will measure real time changes in blood pressure, heart rate as well as changes in extra-aortic pressures within the chest wall. These measurements will be done while subjects snore, have sleep apnea and also during short periods of exposure to treatment. Furthermore our evaluation will be performed in two specific groups with different mutations, one of them known to be more prone to cardiovascular adverse events. This will help determine whether the immediate cardiovascular stress imposed by sleep apnea and snoring depends on the genotype. The findings from this project may explain how sleep apnea and snoring could lead to aortic disease and other cardiovascular problems in Marfan syndrome, and the knowledge may extend to persons with similar connective tissue diseases like Loeys-Dietz syndrome, vascular type Ehlers- Danlos syndrome and Arterial tortuosity syndrome who may also have sleep apnea or snore.
This study will offer a better understanding of the behavior of aTAA from a biomechanical perspective and the factors that influence rupture/dissection risk. We ultimately envision creation of a tool that would provide physicians caring for Marfan patients a more objective and accurate individualized assessment of aneurysm rupture/dissection risk, and better guide the decision of when elective surgical repair should be performed. The results of this research will bring great benefit to people with Marfan syndrome, as well as any other population at risk for developing aortic aneurysms, as the goal is to reduce the unnecessary loss of life from aortic rupture and dissection.
2018 Clinical Grants
Dianna Milewicz, MD, PhD, UTHealth McGovern Medical School, $100,000 2-year Clinical Grant. Asprosin’s Role in the Appetite and Progeroid Appearance of Marfan Lipodystrophy Syndrome and Neonatal Marfan Syndrome Patients
Patients with Marfan syndrome (MFS) have specific symptoms affecting the heart and blood vessels, eyes, and bones. Some MFS patients, in particular those diagnosed with Neonatal Marfan syndrome (nMFS) or Marfan lipodystrophy syndrome (MLS), not only have these complications of MFS, they also have an excessively lean, aged appearance. Our recent discovery of a hormone named asprosin has shed some light on why these patients might have issues maintaining their weight. The goal of this project is to determine if the lean, aged appearance of patients with nMFS is due to decreased amounts of asprosin, and confirm decreased food intake in both nMFS and MLS patients. These studies have the potential to provide the basis of a clinical study to determine if the giving asprosin improves food intake and the lean and aged appearance of patients with MLS and nMFS patients.
Melissa Russo, MD, Women & Infants Hospital of Rhode Island, $100,000 2-year Clinical Grant. Pregnancy and other Reproductive Outcomes in Women with Genetic-Predisposition for Aortic Dissection
Women with Marfan syndrome and the related disorders of Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, Turner syndrome, bicuspid aortic valve and familial thoracic aortic dissection, are at increased for poor outcomes during pregnancy. Despite awareness that these women are at increased risk for problems during pregnancy, there is a critical knowledge gap regarding the factors that contribute to these poor outcomes and among these women how to identify those at highest risk prior to a catastrophic event. To achieve our goal of determining the factors related to poor outcomes in pregnancy, we aim to construct an infrastructure for a multi-center, pregnancy consortium for women with a genetic-predisposition for aortic rupture. Information about pregnancy in women with Marfan syndrome and related disorders will be extracted from medical records and patient interviews. This consortium will move towards the goal of filling the critical knowledge gap about maternal and fetal factors that identify the highest-risk women for poor pregnancy outcomes and eventually allow for creation of a risk-calculator to better predict women at highest-risk for poor outcomes in pregnancy. .