2019 Research Grants
Respiratory failure in infants with neonatal Marfan syndrome and recurrent lung collapses are serious complications. More interventions are needed that can prevent the development of or reverse these impairments. This laboratory has developed a mouse model of Marfan syndrome that has enhanced lung injury and associates with the development of emphysema. Using this model we found that the level of a major antioxidant (superoxide dismutase 3 (SOD3) is reduced. This antioxidant usually binds to the fibrillin-1 in the extracellular matrix. We plan to study how the reduction of SOD3 expression corresponds to this injury. We hope to determine whether treatment with antioxidants can prevent or reverse the injury and improve emphysema in the model. These studies will provide critical pilot data showing a rational target for treatment of Marfan associated lung disease.
It is very surprising that almost nothing is known about how dietary interventions affect relevant tissues and organs in patients with Marfan. In a recent study, we identified diet specific differences in total body weight gain, survival rate, and glucose metabolism in two mouse models of Marfan compared to control mice. Importantly, some of these alterations are different between male and female mice. This data suggest that diet composition may affect the health and function of adipose (fat) and cardiovascular tissue in Marfan in a different way than in the general population. Our goals in this proposal are to test well-defined diets in the Marfan mouse models, including a high fat Western diet, a high carbohydrate diet that reflects intake of sugar-rich drinks and foods, and a high fiber diet. We will monitor the development and function of fat tissue and the formation of aneurysms in the aorta. This study in mice could provide the basis for further analysis of diet interventions in individuals with Marfan. This may, in the longer term, provide personalized dietary guidelines for Marfan patients, which may improve fat tissue deposition and function, and may reduce the development of aortic aneurysms.
Thoracic aortic aneurysms are a significant, and potentially lethal, feature of Marfan syndrome characterized by downregulation of smooth muscle contractile proteins and upregulation of synthetic proteins. This switch is orchestrated by Histone Deacetylase 9 (HDAC9), whichis upregulated in Marfan aortopathy. Our laboratory will be examining the role of the non-coding microRNA-204 (miR-204) in structural vascular disorders that has the ability to decrease expression of HDAC9 and possibly reverse these effects . The study may identify miR-204 as a therapeutic strategy to counter the smooth muscle dysfunction in Marfan aortopathy.
Clinical Research Grant
Evidence suggests that individuals with connective tissue conditions such as Hypermobility Ehlers-Danlos Syndrome (hEDS) and/or Hypermobility Spectrum2 Disorder (HSD) suffer from low bone mineral density (BMD) as well as gastrointestinal (GI) symptoms. The primary objective of this study is to determine the frequency and severity of GI symptoms compared to bone mineral abnormalities in patients with hEDS and HSD. The secondary objective is to determine the relationship between patients’ GI symptoms and their energy balance and the effect that relationship may have on BMD. This will be the first study to investigate how gastrointestinal distress measured by a qualitative assessment tool influences nutritional intake and the effect it may have on BMD. This will help establish future interventional research projects that may lead to new therapies for patients with hEDS and HSD who suffer from GI complications.
Based on limited evidence, patients with Marfan syndrome are restricted from certain physical activities, including contact sports, dynamic sports and isometric exercise. Families often interpret this caution as applying to almost all exercise, resulting in many patients with Marfan being sedentary. This lack of exercise likely has detrimental effects including weakness, deconditioning, and joint pain. Depressive symptoms are also not uncommon in Marfan, and may be exacerbated by guidance to avoid exercise. To date, as far as we are aware, there are no published controlled studies on the effects of dynamic exercise in children and young adults. A published study in mice and another adult rehabilitation study both suggest that moderate exercise may actually protect the aorta and myocardium and provide other health benefits in patients with Marfan. Given the significant paucity of data currently existing, and the recent optimistic findings, we plan to conduct a pilot trial of moderate dynamic exercise in adolescents and young adults with Marfan.
Our goal is to evaluate the effects of a moderate dynamic exercise program on measures of cardiovascular, muscular, and mental health in adolescents and young adults with Marfan. We plan to perform a randomized pilot study to calculate effect estimates to perform a larger multicenter study. Our objective is to 1) randomize 20 patients with Marfan age 12-21 years to current status (controls) versus a moderate dynamic exercise intervention, then 2) allow the control group patients to undergo the exercise intervention. We will then compare outcomes between both the intervention and control groups, and between the baseline and post-intervention states. Our hypothesis is that the intervention of a moderate exercise program introduced by a licensed physical therapist will result in improvement in cardiovascular status, muscular health, and mental health without detrimental effects on the aortic wall.
Early Investigator Grant
The severity of aortic dilation and risk for aortic dissection is frequently variable between individuals and even between relatives who have the same genetic mutation. There is significant genetic variation that exists across humans and it is possible that some of these genetic changes may be impacting the differences in TAA severity that exist between individuals. This lab recently identified a common genetic change in coenzyme Q which may be a candidate genetic modifier in TAA. This study will use a well-developed human TAA biobank to define the functional role of molecule in aorta, determine the effects of the variant, and determine how it interacts with a complex of molecules that cause oxidant stress. The results are directly applicable to human biology, which is important given the goal to understand genetic factors that control human TAA.
2019 Victor McKusick Fellowship Grant
In search for new genes that cause thoracic aortic aneurysms (TAA) that can lead to new disease insights, the lab recently identified changes in Importin 8 (IPO8). This is a novel cause of a TAA syndrome that is clinically highly reminiscent of Marfan syndrome, Loeys-Dietz syndrome, and Shprintzen-Goldberg syndrome. Patients present with childhood-onset TAA, global developmental delay, facial features, joint laxity, neonatal low muscle tone, chest deformity, and hernia. Very little is known about IPO8, except that it encodes a protein that is involved in shuttling proteins from the cytoplasm to the nucleus known to be involved in the pathway of these conditions. The study will investigate the IPO8-related disease mechanisms using patient- and control derived skin cells and vascular smooth muscle cells. Additionally the study will identify FDA-approved drugs that can be repurposed to (IPO8-related) TAA therapy.
Our lab has identified mutations in one gene, actin, as the cause of aneurysms in at least 12-21% of families with inherited aneurysms. The protein that this gene produces is critical for the aorta to contract and relax when blood is pumped through the aorta. Patients with a particular error in the actin gene develop a condition called smooth muscle dysfunction syndrome (SMDS). This syndrome is characterized by the development of aortic aneurysms in childhood that require surgical repair by their late teens and the patients rarely live past the age of 30 years. Our lab is currently developing mice that contain the same mistake in their actin gene as these patients. The goal of this study is to determine the similarities and differences between these mice and mice that have Marfan syndrome. The proposed experiments will demonstrate how aortic disease develops in these actin mutant mice and reveal how similar or dissimilar the process is to that in mice with Marfan syndrome. This information will allow us to test whether drugs that have been proved to be effective in treating aneurysms in patients with Marfan syndrome can also be used to treat patients with SMDS. Therefore, our results may ultimately identify or lead to the design of new drugs that benefit all patients with aortic aneurysms.