2016 Grant Recipients
Victor A. Mckusick Fellowship Grant
Maryline Abrial, PhD, Massachusetts General Hospital, $100,000 2-year McKusick Fellowship Grant entitled, “Investigating a Novel Genetic Model of Aortic Root Aneurysm in Zebrafish.” Dr. Abrial proposes to introduce a new powerful and clinically-relevant zebrafish model organism. This lab has discovered that zebrafish genetically engineered to lack the function of two genes that control the level of transforming growth factor-beta (TGF-b) exhibit impressive aortic aneurysm in a location that is anatomically equivalent to where human aortas are susceptible to developing aneurysm. They propose to learn if the activation of the TGF-b pathway implicated in human disease will be sufficient for causing the disease in zebrafish. Specifically, because zebrafish larvae are so small and readily available, the lab will be able to screen large collections of small molecules to see if they will prevent or cure aneurysm in zebrafish. Any small molecule that suppresses zebrafish aneurysm could also be tested in mice and eventually humans to learn if they will prevent and/or reverse aneurysmal disease.
Early Investigator Grants
Prashanth Vallabhajosyula MD, MS, University of Pennsylvania, $75,000 2-year Early Investigator Grant entitled, “Plasma Endothelial Specific Exosome Profiling in Marfan Syndrome.” Dr. Vallabhajosyula proposes to identify biomarkers by the isolation of small vesicles, i.e. exosomes. Utilizing exosome profiling, they will be able to determine if there is a molecular signature that can be to used monitor aneurysm growth and whether this will correspond to imaging results. Additionally, they will investigate what happens to the profile when patients are on medical therapy and determine if profiling can used to monitor the effects of medical therapy.
Rouf Rosanne MD, Johns Hopkins School of Medicine, $75,000 2-year Early Investigator Grant, entitled, “Using an Established Marfan Syndrome Mouse Model to Understand Mitral Valve Prolapse Pathogenesis.” Dr. Rouf will investigate the mitral valve prolapse (MVP) leading cause of morbidity and mortality in infants and children diagnosed with Marfan before age 4. The goal of this proposal is to uncover the mechanisms of Marfan MVP and find treatments that halt or reverse the progression of existing mitral valve disease.
Dr. Suneel Apte, MBBS, DPhil, Cleveland Clinic, $100,000 2- year Faculty Grant entitled, “Fibrillin Microfibril Regulation by ADAMTSL3.” Dr. Apte will investigate the interaction between fibrillin-2 and a group of proteins called ADAMTS. If this interaction is altered because of mutations found in the ADAMTS proteins, there is speculation that this may lead to Beals syndrome, also known as congenital contractural arachnodactyly (CCA), a Marfan related disorder. It may also lead to the muscle weakness and loose joints seen in Marfan syndrome. This study proposes to generate ADAMTS mutant mice and then analyze their cells and tissues.These studies will help determine what impact ADAMTS proteins have on fibrillin-2 in particular and fibrillin microfibrils.
Seda Tierney, MD, Stanford University and Mitra Esfandiarei, PhD, Midwestern University, $100,000 2- year Faculty Grant entitled, “Children and Adolescents with Marfan Syndrome: 10,000 Healthy Steps and Beyond.” Drs. Tierney and Esfandiarei propose to determine if regular exercise improves aortic health in adolescent Marfan syndrome patients and Marfan syndrome mice, and increases use of active coping skills in Marfan syndrome patients.
Aortic dissection is the most life-threatening complication of Marfan syndrome, characterized by weakening of the aortic wall due to fragmentation of elastin fibers. To date, clinical emphasis has been on what exercises to avoid, due to high risk of aortic dissection, rather than promoting regular exercise. It is also common for Marfan syndrome patients to have sedentary lives due to self-imposed limitations and difficulty in coping with their diagnosis. Preliminary data in Marfan syndrome mice has demonstrated that daily exercise can improve aortic health by reducing elastin fiber fragmentation and aortic stiffness. The proposed research is significant since a new focus on promoting regular exercise will be a paradigm shift in clinical care of these patients with conceivable benefits.
Zhiyong Lin, PhD, Case Western Reserve University, $100,000 Faculty Grant entitled, “Allosteric Activation of PP2A to Limit the Progression of Aortic Aneurysm in Marfan Syndrome.” This laboratory will investigate the development of new pharmacologic therapies for aortic aneurysm. Their preliminary studies indicate that activation of a genetic factor termed protein phosphatase 2A (PP2A) could potently inhibit the progression of aortic aneurysm – the main cardiovascular complication of Marfan syndrome that causes high morbidity and mortality in patients. Studies in this proposal aim to further characterize the inhibitory effects of PP2A activation in the pathogenesis of ascending aortic aneurysm and dissection. Results gleaned from these studies may facilitate the development of novel therapies to ameliorate the ascending thoracic aortic aneurysm progression.
Jessica Wagenseil, DSc, Washington University, $100,000 2-year Faculty Grant entitled, “Arterial Tortuosity and Aneurysms.” This study will investigate the relationship between arterial tortuosity and the risk of aortic dissection. Since acute dissections do occur on thoracic aortic aneurysms that do not meet surgical criteria and rupture risk is only weakly correlated with aneurysm diameter, arterial tortuosity has been suggested as a useful indicator of TAA progression. Increased arterial tortuosity is associated with increased TAA diameter and a younger age for required surgical intervention. It is not known if arterial tortuosity can be used as a predictive indicator of aneurysm growth and/or the risk of dissection and rupture. This study will determine if increased arterial tortuosity correlates with increased TAA size and/or growth rate. They will also determine if decreased aneurysm size and/or growth rate with captopril treatment correlates with decreased arterial tortuosity. These studies may lead to new non-invasive imaging procedures that can be used to predict TAA pathogenesis and improve surgical intervention guidelines for patients with CTDs, such as Marfan syndrome.