Grant: $796,712 - National Institutes of Health - Sep. 1, 2009
No votes have been cast for this award yet
Award Description: This two-year proposal is designed to establish a research framework of excellence that can be used to develop new translational insights into the mechanism of heart valve disease with the aim of improving therapy. Our specific goal is to understand the impact of genetic based disease on mitral valve biology whose clinical expression and prognosis is strongly associated with progressive, degenerative changes in valve structure and function, often requiring surgical intervention. The proposed alliance of the investigative team is required to move genetic findings into model systems to be used to understand mechanism(s) and to identify potential translational therapies. In addition, this network is designed to provide junior investigators (Assistant Professors and Post-doctoral Fellows) opportunities for career growth including experience working on translational projects with an international network of senior investigators. It is expected that this project will also lead to full independence and new funding resources. The focus of the studies presented in the supplemental proposal pertain to mitral valve disease. Originally described in the 1960s, MVP(mitral valve prolapse) is characterized by the systolic displacement or billowing of the mitral leaflets into the left atrium and is often accompanied by mitral regurgitation (MR). MVP is the most prevalent of all mitral valve diseases, affecting as many as 2.4% of the population and is the leading cause for mitral valve repair operations. Mitral leaflets in affected individuals exhibit excess tissue growth with myxomatous changes characterized by altered collagen and elastin composition, proteoglycan accumulation, and disruption of the fibrous backbone. Many of the patients with MVP develop serious complications, including bacterial endocarditis, ruptured chordae tendineae, progressive mitral regurgitation, arrhythmias, and even sudden death. Determination of the molecular basis of MVP is important because the disease often manifests clinically after-birth as a severe cardiac event. Early intervention in susceptible individuals could potentially prevent progression to a clinically severe stage. The design and application of such interventions can be promoted by genetic studies in two ways. First, knowledge of the molecular defects that cause MVP will eventually lead to an understanding of its pathogenesis, with the potential, in turn, to lead to a rational therapy that will likely be applicable to all cases of MVP. Second, establishing the genetic basis of MVP can also refine the echocardiographic evaluation of young individuals who could potentially benefit from early intervention in the hope of reducing disease progression. Although the etiology of MVP is currently unknown, the study of how mutations in filamin-A lead to an X-linked form of non-syndromic MVP promises to provide new insights into how genetic defects that alter valve development eventually lead to MVP. Thus, a more thorough comprehension and appreciation of the morphogenetic events that occur during valve maturation is needed to provide a foundational understanding of how genetic defects lead to MVP. The investigative team assembled through the use of these supplemental funds will prove monumental towards understanding the pathogenesis of MVP and may ultimately lead to rationale drug therapies.
Project Description: In our original application, we propose to show how genetic information taken from screening patients with a documented valve disease can be used to establish chromosomal linkage loci and candidate gene mutations whose mechanisms can then be determined using basic molecular and cellular studies including genetically engineering animal models. To bring the cycle full circle, we will use data obtained from in vivo and in vitro studies to identify potential therapeutic targets. For the T-1 proposal, the validity of the ?Cycle of Discovery? as a translational paradigm will be tested by focusing on a specific gene ? Filamin A ? which we have found to be mutated in patients with mitral valve prolapse (MVP). Determining the molecular basis of MVP is important due to clinical manifestation in the 5th or 6th decade of life through presentation as a severe cardiac event. Our unifying hypothesis is that mutations in Filamin-A cause small alterations in molecular circuitry during valve development which, over time, gradually lead to severe valvulopathology. Thus, this Translational (T1) Supplement emphasizes one of the 3 major reasons we proposed in the parent grant for studying cardiovascular development, i.e. that development mechanisms underlie adult heart diseases. The overall anticipated outcome is when the mechanisms underlying MVP are discovered, we may be able to intelligently and rationally develop novel therapies to better treat those individuals with this disease.
Jobs Summary: Research Specialist II (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 1, 2009. Help expand these official descriptions using the wiki below.