The Role of Proteolysis in Cardiac Development and Disease

Doctor's Name: 
Ibrahim Domian
Massachusetts General Hospital

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

(Total Grant Amount $154,000; CHF portion = $47,567.52)

Heart defects are the number one cause of infant mortality worldwide and a major risk factor for adult cardiovascular problems. Understanding how the heart forms is important to treat these types of defects. The formation of human organs is not only controlled by when and where proteins are made, but also how they are degraded. We have shown that a gene called Asb2 controls degradation of specific proteins in the developing heart. Among the known Asb2 targets are Filamin proteins that form the heart cytoskeleton (the inner support structure of heart cells). In this proposal we investigate how Asb2 regulated degradation of filming and other proteins controls cardiac development. This will help us understand how the heart is normal formed and how this process goes wrong in disease.

Asb2 is a key regulator of protein degradation of multiple other proteins. We show that Asb2 is necessary for the normal function of heart muscle cells and normal development of the embryo. One of the most important proteins that are degraded by Asb2 is the Filamin cytoskeletal protein required for normal cell architecture. Deletion of Asb2 results in the abnormal accumulation of Filamins and ultimately multiple abnormalities in cell function. We wish to understand why protein degradation is important in heart function and which specific targets need to be turned over for normal function. We also examine how protein degradation controls the development of human heart muscle cells and how disruption of this process can contribute to heart disease.

Understanding the processes that govern normal heart formation and when altered can lead to disease will bring us closer to our ultimate goal of a world free of heart problems. Our results will also shed light on the role of proteolysis in human stem cells maturation into functional heart cells, a major limitation for the use of stem cells in heart regeneration. Moreover, since mutations in Filamin genes have been linked to heart disease in humans, understanding how these proteins are regulated will improve our comprehension of how they cause disease and possibly facilitate the use of gene therapy to cure them. Finally, the proteolysis system is an important new target for drug discovery and targeting this pathway will become increasingly important in developing new heart medications.

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