Characterizing an X-Chromosome Locus that Encodes Heart-Specific Noncoding RNAs
Abstract
The topic areas of this application are ?Women?s Heart Disease? and ?Congenital Heart Disease.? Cardiovascular diseases are the Number 1 killer in developed countries. Because the human heart does not have the capacity to repair itself, acute and chronic heart injuries often lead to heart failure. Clinicians and researchers have been trying to develop new therapies for heart diseases, which calls for advanced understanding of factors that contribute to normal heart development and diseases. Cardiovascular diseases (CVD) occur later in women, but around equal number of women and men die each year of CVDs in the United States. Women have much poorer prognosis after heart attack: women are twice as likely as men to die within the first few weeks. Understanding the biological mechanisms behind this has great potential to improve treatment for CVDs. To date, sex hormones (testosterone and estrogen), difference in metabolism, the number of X-chromosome (men have XY while women have XX) and other factors are speculated as the potential reasons. While the reasons are likely complex, genes encoded by the X-chromosome is a great focal point. My lab recently identified an X-chromosome locus that is specifically activated during embryonic heart development. This X-chromosome locus does not encode any protein, but produces special RNAs called miRNAs and LncRNAs. Strikingly, this locus produces eight different miRNAs and LncRNAs. Scientists have just started to appreciate that these RNA species, like proteins, can be important regulators of normal development, and their mutations can contribute to human congenital diseases. We hypothesize that this X-chromosome locus is important for normal cardiovascular system development and that mutations affecting this locus lead to human congenital heart diseases. We will use the state-of-the-art Cas9/CRISPR technology to create a series of deletions spanning this locus. Our aim is to study the function of these non-protein-coding RNAs by completely removing them from the cells. We will remove the eight non-protein-coding RNAs as individuals or combinations. We will study if cells can still become heart muscle, even when the non-protein-coding RNAs are absolutely absent. Consequently, we will not only answer if these RNAs are critical players in heart development, but also answer how these RNAs interact with each other. At the conclusion of this study, we look to establish that this X-chromosome locus play critical roles in heart muscle cell formation and in cardiovascular gender differences. If such important roles are established, the non-protein-coding RNAs may be developed into drugs to treat cardiovascular diseases. As we as a research community have just started to appreciate the function of non-protein-coding RNAs, experience gained by using a cutting-edge technique (Cas9/CRISPR) to finely dissect a complex loci may be used by others to analyze other non-protein coding RNAs. Therefore, this study will not only help our understanding of human heart diseases, the technical advancement will also be broadly impactful.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710313
Entities
People
- Yu Liu
Organizations
- United States Army
- University of Houston