Based on genetic and cellular discoveries made in the PI's lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal show that mutations in the DCHS1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. These discoveries have led to the identification of cilia as a critical and unexplored area of valve development, and are the basis for this proposal. Our studies will provide unique opportunities to answer questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the-art biological and genetic approaches. Valvular heart disease is a serious clinical problem, affecting 5-7% of the human population. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. There are no known non- surgical cures for this group of disease. The proposed work capitalizes on previously unrecognized genetic data collected from heart valve disease patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to valvular heart disease patients.

Public Health Relevance

Little is known regarding the etiology of valve disease. Uncovering the genetic causes for valve disease will provide key insight into mechanisms that contribute to valve development and allow us to study why valve disease happens. Based on our genetic, developmental and molecular discoveries, our goal for this proposal is to examine new mechanisms for valvular development and their link to the pathogenesis of cardiac valve diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Evans, Frank
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Medical University of South Carolina
Anatomy/Cell Biology
Schools of Medicine
United States
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Le Tourneau, Thierry; Le Scouarnec, Solena; Cueff, Caroline et al. (2018) New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study. Eur Heart J 39:1269-1277
Toomer, Katelynn A; Fulmer, Diana; Guo, Lilong et al. (2017) A role for primary cilia in aortic valve development and disease. Dev Dyn 246:625-634
Lobo, Glenn P; Fulmer, Diana; Guo, Lilong et al. (2017) The exocyst is required for photoreceptor ciliogenesis and retinal development. J Biol Chem 292:14814-14826