Translational Targets of Ribosomal Protein RPL13 as Novel Cardiac Drivers of Differentiation in Drosophila and Human iPSCs: Implications for CHD
Abstract
Many people in the United States are born with Congenital Heart Disease (CHD; FY20 PRMRP Topic Area), a condition where hearts are malformed and function abnormally disrupting the flow of blood. This can reduce one’s quality of life and ability to reach full potential. In most individuals with heart defects, doctors do not know the cause of the disease. This diminishes their ability to offer treatments to help patients address risks and limitations imposed by their condition. While many CHD cases are detected at birth, in some cases, individuals display no symptoms initially but through external stress (possibly though military training, stresses of deployment, or normal aging) can worsen underlying defects in adulthood, creating complications that lead to heart dysfunction. The experiments proposed in this application will deepen our understanding of how the cells of the heart develop normally and what could go wrong when the heart forms improperly, resulting in CHD. Our studies focus on a gene called large ribosomal subunit 13 (RPL13), which we believe plays a critical role in the creation of specialized cells of the heart. In a number of CHD patients, changes in the gene have been detected, but how these changes could lead to abnormal heart cells and CHD has not been previously examined. RPL13 is challenging to study because it is involved in critical processes in the cell that are important in keeping cells alive. But, we believe that with the proper tools and study design, we can demonstrate that RPL13 has a very important and specialized role in creating functioning heart cells, and if we disrupt the function of RPL13, this can lead to an abnormal heart cell and contribute to CHD. Uniquely, our toolset includes the use of two simple yet powerful cardiac models, Drosophila heart and human cardiac cells, and together their simplicity will lead to data that will be more easily interpretable, which is central considering CHD is such a complex disease. Specifically, the questions I will address include: What is the role of the gene RPL13 in creating specialized heart cells? If I disrupt the function of RPL13, what happens to the heart cells and how are they different from normal cells? And lastly, what other genes and proteins does RPL13 interact with to drive normal heart formation? By addressing these questions, we will develop a clearer and more informed understanding of the various players involved in heart formation. When we better understand how the heart forms, we can figure out exactly what goes wrong in the patients with abnormally formed hearts. By identifying new genes involved in causing CHD, more patients will receive an exact diagnosis and possibly doctors will be able to predict how a patient’s specific condition will affect their prognosis. In this light, treatment can be developed specific to the patient to improve their quality of life. Our knowledge of heart development will expand and have far-reaching impacts on patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110159
Entities
People
- Analyne M. Schroeder
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army